immunology and microbiology topics notes

immunology and microbiology topics notes

1. What is Immunity?
Immunity is the ability of an organism to resist a particular infection or toxin by the action of specific
antibodies or sensitized white blood cells. The word ‘immunity‘ came from the Latin word “immunis which
means “exempt”. Thus, immunity is a state of protection from infectious disease. There are two types
of immunity: innate and acquired immunity.
Immunity results from the combined activities of many different cells, some of which patrol the body,
whereas others will concentrate in lymphoid organs, such as the bone marrow, thymus, spleen, and lymph
nodes. Together, these dispersed cells and discrete organs form the body’s immune system. The main
function of the immune system is to prevent or limit infections by pathogenic microorganisms, such as
bacteria, viruses, parasites, and fungi.
The collective and coordinated response of the immune system to foreign substances is known as
the immune response. The recognition of microorganisms and foreign substances is the first event in
immune responses of a host.
Types of immunity
Immune responses are broadly divided into two categories:
 innate (natural), or
 adaptive (or acquired) immunity.
Types of immunity
Both types of responses depend on the ability of the body to distinguish between “self”(particles, such as
proteins and other molecules, that are a part of, or produce by, our body) and “nonself” (particles that are
not made by our body and are recognized as potentially harmful) materials.
First, lets start with innate immunity…
Innate immunity
Innate immunity is the resistance that an individual possesses by birth and is genetically transfer from one
generation to the next. It is always general, or nonspecific. Further, it is an immediate type of immune
response.
It consists of cellular and biochemical defence mechanisms that respond rapidly to infection. Also, they
provide the body with the first line of defence.
The factors that may influence innate immunity include:
 age,
 hormonal level, and
 nutritional status of the host.
Extremes of age(either too young or too old) make an individual highly susceptible to various infections. In
addition, individuals with certain hormonal disorders become increasingly susceptible to infection. For
example, pregnant women are more susceptible to many infections due to higher level of steroid (hormones)
during pregnancy.
The principal components of innate immunity are:
1. physical and chemical barriers,
2. phagocytic cells (neutrophils, macrophages), dendritic cells, and natural killer (NK) cells,

2. 3. blood proteins, including members of the complement system and other mediators of inflammation,
4. cytokines that regulate and coordinate many of the activities of the cells of innate immunity.
Innate immunity may be classified as:
 individual immunity,
 racial immunity, and
 species immunity.
Individual Immunity
Individual immunity is that in which one individual of certain race or cast is resistant to an infection while
other individuals of the same race or cast are susceptible to the same infection. In other words, if someone
has the same racial background but experience fewer or less severe infections than other individuals of the
same race, in this situation, it is known as individual immunity.
For example, children are more susceptible to diseases such as measles and chickenpox, while old
individuals are susceptible to other diseases like pneumonia.
Racial immunity
Racial immunity is that in which one race is susceptible while the other race is resistant to the same
infection. For example, races with sickle cell anaemia are immune to malaria. Similarly, individuals with a
hereditary deficiency of glucose-6-phosphatase dehydrogenase are less susceptible to infection by
Plasmodium falciparum.
Species Immunity
Species immunity denotes a total or relative resistance to a pathogen shown by all members of a particular
species. For example, chickens are resistant to Bacillus anthracis, rats are resistant to Corynebacterium
diphtheriae, whereas humans are susceptible to these bacteria.
Anatomic, physiological and metabolic differences between species determine species immunity. However,
the exact reason for such type of immunity is not clear.
Mechanism of innate immunity
It works on two basic principles:
1. Either it kills invading microbes, or
2. it activates acquired immunity.
The innate immunity is primarily dependent on four types of defensive barriers:
1. anatomical barriers,
2. physiological barriers,
3. phagocytosis, and
4. inflammatory responses.
Anatomical barriers
Anatomical barriers include skin and mucous membrane. They are the most important components of innate
immunity. They act as mechanical barriers and prevent the entry of microorganisms into the body.
Skin: the intact skin prevents the entry of microorganisms. For example, breaks in the skin due to scratches
or wounds cause infection. Skin secretes sebum, which prevents the growth of many microorganisms. The
sebum consists of lactic acid and fatty acids that maintain the pH of skin between 3 and 5, and this pH
inhibits the growth of most microorganisms.

3. Mucous membrane: it forms a large part of the outer covering of gastrointestinal, respiratory, genitourinary,
and many other tracts of human. Saliva, tears, and mucous secretions wash away potential invading
microorganisms. Hence, prevents their attachment to the initial site of infections. These secretions also
contain antibacterial or antiviral substances that kill these pathogens.
Physiological Barriers
The physiological barriers that contribute to innate immunity include the following:
 Gastric acidity: very few ingested microorganisms can survive the low pH of stomach contents.
 soluble mediators
1. Lysozyme: a hydrolytic enzyme found in mucosal secretions and in tears, attack on
peptidoglycan layer of the bacterial cell wall.
2. interferons: it comprises a group of proteins secreted by virus-infected cells. They have the ability
to bind to the nearby cells and induced a generalized antiviral state.
3. complement: it is a group of serum-soluble substances that when activated damage the cell
membrane of the pathogenic organisms.
Phagocytosis
It is another important defence mechanism of innate immunity. Phagocytosis is a process of ingestion of
extracellular particulate material by certain specialized cells, such as blood monocytes, neutrophils, and
tissue macrophages.
Key steps in phagocytosis:
 bacterium attaches to pseudopodia
 ingestion of bacterium, forming phagosome
 phagosome fuses with lysosomes
 lysosomal enzymes kill and digest bacterium
 and lastly, the release of digested product from the cell.
Inflammatory responses
When the outer barriers of innate immunity, skin and other epithelial layers are damaged, the resulting innate
responses to infection or tissue injury can induce a complex cascade of events known as the inflammatory
response. Generally, the end result of inflammation may be the activation of a specific immune response to
the invasion or clearance of the invader by components of the innate immune system.
difference between innate and
acquired immunity

4. Acquired/Adaptive Immunity
It is the more specific component of immunity. It is also known as acquired immunity. Acquired immunity is
highly adaptive and is capable of specifically recognizing and selectively eliminating foreign
microorganisms and macromolecules, i.e., antigens.
It occurs after exposure to an agent and will mediate by antibodies as well as T lymphocytes (helper T cells
and cytotoxic T cells). Moreover, it has immunologic memory and a remarkable capability of discriminating
between self and nonself antigens.
Once an antigen has been recognized by the cells of the acquired immune system, the response to it is
specific and can be repeated. In most cases, the acquired immune response improves with repeated
exposure. The immune response to the second challenge occurs more quickly than the first, is stronger, and
is often more effective in neutralizing and clearing the pathogen.
Characteristics
Adaptive or acquired immunity displays four types of characteristics attributes:
1. Antigenic specificity
2. diversity
3. immunologic memory
4. self and non-self recognition
Antigenic specificity: permits it to distinguish subtle differences among antigens. In addition, antibodies can
distinguish two protein molecules that differ in only single amino acid.
Diversity: the immune system is capable of generating tremendous diversity in its recognition molecule,
allowing it to recognize a variety of billions of unique structure. In general, an adaptive system can recognize
a single type of organism and can differentiate among those with minor genetic differences.
Immunologic memory: adaptive immunity can store the information of all immunologic sequences when
encountered by a pathogen. When there is a second encounter to the previous pathogen produces a
heightened state of immune reactivity.
Self and non-self recognition: Normally, the immune system responds to only foreign antigens. It indicates
that it is capable of self and non-self recognition.
Types of adaptive immunity
Adaptive or acquired immunity can be of two types:
1. Active immunity
2. Passive immunity
Active immunity
Active immunity is the immunity that develops after exposure to a foreign antigen. Though it takes time to
develop, it is long-lasting and it is the major advantage of the active immunity. Further, it is of two types:
1. natural active immunity
2. artificial active immunity
Natural active immunity
It is a type of immunity that develops after natural infection. For instance, if a person will encounter a
pathogen and fall ill. Now, on the second encounter with the same pathogen, he will not develop any sign of
infection because he developed antibodies against the pathogen after his first encounter. Therefore, he will

5. be immune to it. Such natural immunity is longlasting. For example, individuals suffering from smallpox
become immune to the second attack of the disease.
Artificial active immunity
It is a type of immunity that develops after vaccination. Today, there are various vaccines available against a
wide number of pathogens. These are live vaccines(non-virulent), killed vaccines, or vaccines containing
bacterial products.
Mediators of active immunity
There are two mediators of Active immunity :
1. Humoral
2. cell-mediated immunity
Humoral immunity
It is mediated by antibodies present in the blood and mucosal secretions, which are produced by B
lymphocytes. The antibodies will be secreted by a subset of lymphocytes known as B cells.
Humoral immunity is the principal defence mechanism against extracellular microbes and their toxins
because secreted antibodies can bind to these microbes and toxins and assist in their elimination.
Cell-mediated immunity (cellular):
It is mediated by both activated TH cells and CTLs(Cytotoxic T Lymphocytes). Intracellular microbes, such
as viruses and some bacteria, survive and proliferate inside phagocytes and other host cells, where they are
inaccessible to circulating antibodies. Defence against such infections is a function of cell-mediated
immunity.
Cytokines secreted by TH cells activate various phagocytic cells, enabling them to phagocytose and kill
microorganisms. CTLs play an important role in killing virus-infected cells and tumor cells.
Passive Immunity
When immunity is conferred on an individual by transferring serum or lymphocytes from a specifically
immunized individual, then this type of immunity is called passive immunity. Recipient of such a transfer
becomes immune to the particular antigen.
Like active immunity, Passive immunity is also of two types:
1. Natural, and
2. artificial
Natural passive immunity
When IgG pass from mother to fetus during pregnancy, natural passive immunity develops. IgG antibody
produced in mother can cross the placenta and protects fetus up to 6-month-old age.
(Read article on antibodies for information on various classes of antibodies)
Natural passive immunity will also develop by the passage of IgA from mother to newborn during
breastfeeding.
Artificial passive immunity

6. It is induced in an individual by administration of preformed antibodies, generally in the form of antiserum,
raised against an infecting agent. Administration of these antiserum makes large amounts of antibodies
available in the recipient host to neutralize the action of toxins.
Immediate availability of a large number of antibodies is the main advantage of passive immunity.
Disadvantages
 the short lifespan of introduced antibodies
 possibility of hypersensitivity reaction against antibodies prepared in other animal species.
Sources and links
Textbook of microbiology and immunology by Subhash Chanda Parija, chapter 11, Immunity
Cellular ad molecular immunology, seventh edition, by Abul K. Abbas, Andrew H. Lichtman, chapter no. 1
Also, Kuby immunology, 7th edition, chapter no. 5


Cells of the Immune System
All the cells of the immune system arise from a single hematopoietic stem cell (HSC). Actually, HSC can give
rise to three different types of progenitor cells, namely, lymphoid progenitor, myeloid progenitor and
erythroid progenitor. Basically, lymphoid and myeloid progenitors give rise to immune cells and erythroid
progenitor gives rise to other types of blood cells.
In this article, we will discuss lymphoid and myeloid progenitors in detail.

1. LYMPHOID PROGENITORS : they give rise to three types of immune cells.
1. B cells
2. Natural killer cells
3. T cells
2. MYELOID PROGENITORS : they give rise to two types of immune cells that have further sub-classes.
1. Granulocytes
 Eosinophils
 basophils
 Neutrophils

7.  Mast cells
2. Unknown cells
 Antigen-presenting cells (Monocytes)
 dendritic cells
 macrophages
3. ERTHROID PROGENITORS
1. Megakaryocytes
 platelets
2. Erythroblasts
 erythrocytes (RBCs)
Myeloid cells and NK cells are members of the innate immune system and are the first cells to respond to
infections. Lymphocytes are members of the adaptive immune response and generate a refined antigen-
specific immune response which also produces immune memory. Macrophages and dendritic cells are
monocytes that have non-granular cytoplasm. Monocytes circulate in the blood for about one to three days,
and then usually enter the body’s tissues, where they differentiate into macrophages and dendritic cells.
LYMPHOID PROGENITORS
Lymphoid progenitors give rise to B cells, T cells and natural killer cells. B cells and T cells fall under
lymphocytes.
Cells of Adaptive Immune System: Lymphocytes
Lymphocytes are ovoid cells, about 8-12 µm in diameter, and are mobile and circulate throughout the body.
The lymphocytes occupy a very special place among the white blood cells that participate in one way or
another in immune reactions due to their ability to interact specifically with antigenic substances and to
react to nonself antigenic determinants. In addition, they also contribute to the memory of the immune
system. Therefore, lymphocytes are the mediators of humoral and cellular immunity. There are various sub-
types of lymphocytes that differ in terms of origin, lifespan, preferred areas of settlement within the
lymphoid organs, surface structure, and function.
They represent 20% to 40% of circulating white blood cells and 99% of cells in the lymph. Lymphocytes
differentiate from stem cells in the fetal liver, bone marrow, and thymus into two main functional classes:
1. T cells
2. B cells
Depending upon where they undergo their development and proliferation, they are grouped into the above
two classes. For example, B cells develop in the bone marrow and T cells develop in the thymus. Hence, they
have named B cells (B derived from bone marrow) and T cells (T- thymus). Both B and T lymphocytes are
structurally alike but functionally different. They are present in the peripheral blood and in all lymphoid
tissues.

8. 1. T lymphocytes/ T cells
T cells are the cells of adaptive immunity.
Role: they participate directly in the immune responses as well as in arranging and regulating activities of
other cells.
Characteristics
1. T-cells develop in the bone marrow but complete their development in the thymus.
2. they represents 65–80% of the circulating pool of small lymphocytes.
3. they can live longer than B cells. Longlasting lymphocytes are particularly important because of their
involvement on immunological memory.
4. T cells are present in the inner subcortical regions but not in the germinal centers of the lymph
nodes.
5. they are different from other lymphocytes as they have a T cell receptor (TCR) on their surface. TCR
do not recognize whole antigens, but instead react only to small fragments of antigens.
6. they can target and selectively destroy virus-infected cells and cancer cells.
7. T cells do not produce any antibody.
Sub-classes
There are two main and two rare sub-classes of T cells:
 MAIN
 Helper T cells (CD4
+
)
 Cytotoxic T cells (CD8
+
)
 RARE
 TREG cells
 γδ T-cells
1.1 Helper T cells (CD4
+)
They are also known as CD4
+
cells. Helper T (Th) cells are mainly present in the thymic medulla, tonsils, and
blood. Basically, they constitute about 65% of peripheral T cells. These cells have no cytotoxic activity and
do not kill infected cells or clear pathogens directly. They instead control the immune response by directing
other cells to perform these tasks.
CD4
+
cells recognize a nonpeptide-binding portion of MHC class II molecules. Hence, CD4
+
T cells are
restricted to the recognition of pMHC class II complexes.
Function

9. 1. These cells help B cells and other T cells to multiply into large clones and carry out their role in
immune response.
2. Th-1 cytokines activate cytotoxic inflammatory and delayed hypersensitivity reactions.
3. Th-2 cells help in the production of interleukins which encourage production of antibodies especially
IgE.
4. Th-2 cytokines are associated with regulation of strong antibody and allergic responses.
1.2 Cytotoxic T cells (CD8
+)
They are also called cytotoxic T (Tc) and suppressor T (Ts) cells. They account for approximately one-third
of all mature CD3+ cells. These are present mainly in the human bone marrow and gut lymphoid tissue. CD8+
T glycoprotein of T cells recognizes a nonpeptide-binding portion of MHC class I molecules. Hence, CD8
+
T
cells are restricted to the recognition of pMHC class I complexes.
Point to remember: Both CD4+ and CD8+ T cells recognize a nonpeptide-binding portion of MHC molecules.
But CD4+ recognize a portion of MHC class II molecules whereas CD8+ recognize the MHC class I molecule
portion.
Function
They perform mainly cytotoxic functions.
1. CD8
+
T cells kill virus infected cells.
2. They also kill tumor cells and allograft cells.
1.3 Regulatory T-cells (TREG cells) or supressor T cells (former name)
They provide tolerance to self-antigens (peripheral tolerance), and prevent the development of autoimmune
disease.
Surface markers: TREG cells possess surface markers such as CD4, CD25 and Foxp3. Deficiency of Foxp3
receptors leads to a severe form of an autoimmune disease known as Immune dysregulation,
Polyendocrinopathy, Enteropathy X-linked (IPEX) syndrome.
1.4 γδ T-cells
They constitute 5% of total T-cells, express γ/δ chains of TCR chains; instead of α/β chains.
 They lack both CD4 and CD8 molecules. Also, they do not require antigen processing and MHC
presentation of peptides.
 They are part of innate immunity as the γδ receptors exhibit limited diversity for the antigen.
 γδ T cells are usually found in the gut mucosa, as intraepithelial lymphocytes (IELs).
 The function of γδ T-cells is not known, they may encounter the lipid antigens that enter through the
intestinal mucosa.
See also:
B lymphocytes (B cells)
B cells acquired their name from their site of maturation, bursa of fabricus in birds and bone marrow in
mammals. Unlike T cells, they can be morphologically distinguished by their synthesis and display of the B-
cell receptor (BCR), a membrane-bound immunoglobulin (antibody) molecule that binds to the antigen.
Each B cell shows a surface antibody with a unique specificity, and each of the approximately 1.5–3
x10
5
molecules of surface antibody has identical binding sites for antigen. B lymphocytes also can improve
their ability to bind antigen through a process known as somatic hypermutation and can generate antibodies
of several different functional classes through a process known as class switching.

10. Ultimately, activated B cells differentiate into effector cells known as plasma cells. They can produce and
secrete large amounts of immunoglobulin but do not express membrane immunoglobulins.
A single cell is capable of secreting from a few hundred to more than a thousand molecules of antibody per
second. Plasma cells do not divide and, although some long-lived populations of plasma cells are found in
bone marrow, many die within 1 or 2 weeks.
B cells are the only cell of the immune system that are specialized to secrete antibodies and, therefore,
constitute the principal mediators of the humoral (i.e., antibody) immune response.
Function
1. Activated B cells (plasma cells) produces large amount of immunoglobulins specific for the epitope
of the antigen.
2. Plasma cells also produces memory cells which remain alive (in resting stage) for months and some
even for years.
Cells of Innate Immune System: Myeloid cells and natural killer
cells
Myeloid progenitors give rise to two types of cells: granulocytes and unknown cells.

1. Granulocytes
Granulocytes are a type of white blood cell that has granular proteins. They comprise 3-8% of WBCs in the
blood. Further, they give rise to four types of granular cells: basophil, eosinophil and neutrophil and mast
cell.
1.1 Neutrophils
Neutrophils are the largest subpopulation of white blood cells (leukocytes). They differentiate in the bone
marrow. After that, neutrophils will move into the peripheral blood and circulate for 7 to 10 hours before
migrating into the tissues, where they have a life span of only a few days.
They are the first cells that act at the site of tissue damage to eliminate pathogens especially bacteria by
phagocytosis. Once in tissues, neutrophils phagocytose (engulf) bacteria very effectively, and also secrete a
range of proteins that have antimicrobial effects and tissue remodelling potential.
1.2 Eosinophils
Eosinophils constitutes 1-3% of circulating white blood cells (leukocytes). They are motile phagocytic cells
that can migrate from the blood into the tissue spaces. Their phagocytic role is significantly less important

11. than that of neutrophils. These cells are present in high concentrations in allergic reactions and during
parasitic infections, including worms.
1.3 Basophils
Basophils are the least common type of granulocyte. Unlike neutrophils and eosinophils, they are
nonphagocytic cells that contain large granules filled with basophilic proteins. Basophils constitute less
than 1% of white blood cells. They release the contents of their granules in response to the binding of
circulating antibodies. Histamine, one of the best-known proteins in basophilic granules, increases blood
vessel permeability and smooth muscle activity. Basophils play key pathogenic roles in allergic reactions.
1.4 Mast cells
Like basophils, they constitute less than 1% of white blood cells. Mast cells mature only after they leave the
blood.
Mast cells are present in a wide variety of tissues, including the skin, connective tissues of various organs,
and mucosal epithelial tissue of the respiratory, genitourinary, and digestive tracts. Like circulating
basophils, these cells have large numbers of cytoplasmic granules that contain histamine and other
pharmacologically active substances. Mast cells also play an important role in the development of allergies.
2. Antigen Presenting Cells (APKs)
Antigen-presenting cells (APCs) include :
1. Macrophages and
2. Dendritic cells.
2.1 Macrophages (accessory cells)
Macrophages are phagocytic cells. These are not antigen-specific and hence also called accessory cells of
the immune system. Monocytes and macrophages are believed to be closely related. The monocyte is
considered a leukocyte in transit through the blood, which when fixed in the tissue will become a
macrophage. They are closely related but there are fine differences too. These are as follows:
1. Macrophages are larger than monocytes. They are atleast 5-10 fold bigger than monocytes.
2. They are different in terms of cellular content too. Macrophages contain more lysozymes, organelles,
enzymes and cytokines.
3. Macrophages produces higher levels of hydrolytic enzymes.
4. Lastly, they have greater phagocytic activity and have a longer life in tissues (months to years).
Functions
Macrophages perform three main functions:
1. Phagocytosis
2. Antigen presentation
3. Cytokine production
2.2 Dendritic cells
Dendritic cells are so named because of their resemblance to neuronal dendrites. Like neuronal dendrites,
they have many long, narrow processes which make them very efficient at making contacts with foreign
materials. Basically, they are bone marrow-derived cells that express class II MHC proteins and present
antigen to CD4
+
T cells.
They act as a messenger between the innate and adaptive immune systems. Dendritic cells are present in
those tissues that are in contact with the external environment. For example, the skin and the inner lining of
the nose, intestine and stomach. Upon activation, they migrate to the lymph node. After that, they interact
with B cells and T cells to initiate the adaptive immune response.

12. Function
1. The main function of the dendritic cell is to process the antigen material and present it on the cell
surface to the T cells.
Natural killer cells (NK)
Natural killer (NK) cells are large granular lymphocytes that constitute 10–15% of total lymphocytes. They are
efficient cell killers and attack some tumor cells and virally infected cells.
Characteristics
1. They are large granular lymphocytes.
2. NK cells develop within the bone marrow and lack T-cell receptor, but possess another set of
receptors called killer activation receptors and killer inhibition receptors.
3. Prior exposure does not increase the activity.
4. Thymus is not required for development.
5. Number remains normal in severe combined immunodeficiency disease.
Function
1. The main function of NK cells is to kill tumor cells.
2. They also kill viras-infected cells.


STRUCTURE OF ANTIBODIES/IMMUNOGLOBULINS
Immunoglobulins are glycoproteins comprises of four polypeptide chain: two identical light (L) and two
identical heavy (H) chains. Further, L and H chains are subdivided into variable and constant regions. The
terms light and heavy refer to molecular weight. The heavy chains are longer whereas light chains are
shorter. Light chains have a molecular weight of about 25,000 Da whereas heavy chains have a molecular
weight of 50-70,000 Da.

The simplest antibody molecule has a ‘Y’ or ‘T’ shape structure which is the most widely recognizable
feature of immunoglobulin structure. All antibody molecules share the same basic structural characteristics
but display remarkable variability in the regions that bind antigens. Because the core structural unit of each
antibody molecule contains two heavy chains and two light chains, every antibody molecule has at least two
antigen-binding sites.
Immunoglobulin (Ig) domain

13. Both the light chains and the heavy chains contain a series of repeating, homologous units. Each unit is
about 110 amino acid residues long, that fold independently in a globular motif that is called an Ig
domain. An Ig domain contains two layers of a β-pleated sheet, each layer composed of three to five strands
of the antiparallel polypeptide chain. However, the number of strands per sheet varies among individual
proteins.
Within the strands, hydrophobic and hydrophilic amino acids alternate and their side chains are oriented
perpendicular to the plane of the sheet.
Heavy chains of immunoglobulins
An immunoglobulin molecule has two heavy chains. Each heavy chain comprises 420–440 amino acids.
Also, each heavy chain binds to a light chain by a disulfide bond and by noncovalent bonds.
The sequences of the heavy-chain constant regions fall into five basic patterns. These five basic sequences
named with Greek letters and these are:
 µ (mu)
 δ (delta)
 γ (gamma)
 ε (epsilon)
 α(alpha).
The heavy chains of a given antibody molecule determine the class of that antibody. For example, IgM
contains µ (mu), IgG contains γ (gamma), IgA contains α(alpha), IgD contains δ (delta), and IgE contains ε
(epsilon). heavy chains. These heavy chains are structurally and antigenically distinct for each class of
immunoglobulin.
In addition, heavy chains exist in two forms that differ at their carboxyl-terminal ends. One form of the heavy
chain anchors membrane-bound antibodies in the plasma membranes of B lymphocytes whereas the other
form is secreted when associated with Ig light chains.
Light chain
An immunoglobulin molecule has two light chains. Each light chain comprises 220–240 amino acids.
Further, the light chain attaches to the heavy chain by a disulfide bond. Unlike heavy chains, the light chains
are structurally and chemically similar in all classes of immunoglobulins. They are of two types:
 Κ (kappa), and
 λ (lambda).
Each immunoglobulin has either two Κ (kappa) or two λ (lambda) chains but never both. In humans, about
60% of antibody molecules have Κ (kappa) light chains and about 40% have λ light chains. The Κ (kappa) and
λ (lambda) chains are present in human serum in a ratio of 2:1.
Each light chain comprises of one V (variable) region Ig domain and one C (constant) region Ig domain.
Variable regions distinguish the antibodies made by one clone of B cells from the antibodies made by other
clones.
Variable and constant region
Each polypeptide chain of an immunoglobulin molecule contains an amino-terminal part and a carboxy-
terminal part. The amino terminal part is called the variable region (V region) whereas the carboxy-terminal
part is called the constant region (C region).

14. The variable regions of both the light and heavy chain are responsible for antigen binding whereas the
constant region of the heavy chain is responsible for various biologic functions. For example, complement
activation and binding to cell surface receptors.
Constant region
The constant (C) region is the carboxyl-terminal of the molecule. It consists of two basic amino acid
sequences. The constant region of the light chain does not have any biological function whereas the
constant region of the heavy chain is responsible for activation of the complement, binding to cell surface
receptors, placental transfer, and many other biological activities.
Moreover, the C region domains are separate from the antigen-binding site and do not participate in antigen
recognition.
Variable region
The variable region consists of 100-110 amino acids at amino-terminal end. This region is different for each
class of immunoglobulins. Basically, the variable regions of both L and H chains have three extremely
variable (hypervariable) amino acid sequences at the amino-terminal end that form the antigen-binding site.
The hypervariable loops are like fingers protruding from each variable domain, three fingers from the heavy
chain and three fingers from the light chain coming together to form an antigen-binding site.
These antigen-binding sites are responsible for specific binding of antibodies with antigens.
Fab fragments (fragment antigen-binding)
It is a region on an antibody that binds to antigens. It comprises one constant and one variable domain of
each of the heavy and the light chain. These domains shape the antigen-binding site, at the amino terminal
end of the monomer.
Fc fragments (fragment crystallizable)
Fc region is the tail region of an antibody that interacts with cell surface receptors called Fc receptors and
some proteins of the complement system. This property allows antibodies to activate the immune system.
How many types of antibodies are there?
Antibodies, also known as immunoglobulins, are of five types.
1. IgG
2. IgA
3. IgM
4. IgD
5. IgE
Lets discuss these types/classes one by one…
IgG
Each IgG molecule consists of two L chains and two H chains linked by disulfide bonds. It has a molecular
weight of 1,50,000 Da and has a half-life of 23 days (longest among all the immunoglobulins). It is a divalent
molecule because it has two identical antigen-binding sites.

15. IgG is the most abundant class of immunoglobulins in the serum, comprising about 80% of the total serum
immunoglobulin. Depending upon antigenic differences in the H chains and on the number and location of
disulfide bonds, there are four subclasses of IgG, namely: IgG1, IgG2, IgG3, and IgG4. They are numbered
according to their decreasing concentrations in serum.
Chiefly, IgG1 makes up most (65%) of the total IgG. IgG2 antibody is directed against polysaccharide
antigens and is an important host defence against encapsulated bacteria.
IgG is the only antibody to cross the placenta and is, therefore, the most abundant immunoglobulin in
newborns. This is an example of passive immunity because the IgG is produced by the mother, not by the
fetus.
to know more about passive immunity…… check notes on types of immunity

Functions
 IgG1, IgG3, and IgG4 are the only immunoglobulins with the ability to cross the placental barrier.
Therefore, they play an important role in protecting the developing fetus against infections.
 IgG3, IgG1, and IgG2, in order of their efficiency, are effective in the activation of the complement.
 It takes part in precipitation, complement fixation, and neutralization of toxins and viruses.
 It binds to microorganisms and facilitates the process of phagocytosis of microorganisms.
IgA
IgA is the second major serum immunoglobulin, comprising nearly 10–15% of serum immunoglobulin. It has
a half-life of 6–8 days. In addition, it is the main immunoglobulin in secretions such as colostrum, saliva,
tears, and respiratory, intestinal, and genital tract secretions. Moreover, IgA occurs in two forms:
 serum IgA: It is present in the serum and is a monomeric molecule with a molecular weight of 60,000
Da. It has two subclasses, IgA1 and IgA2.
 secretory IgA: It is a dimer or tetramer and consists of a J-chain polypeptide. Secretory IgA is the
major immunoglobulin present in external secretions, such as breast milk, saliva, tears, and mucus of
the bronchial, genitourinary, and digestive tracts.
Functions
 It protects the mucous membranes against microbial pathogens. Because it is polymeric, secretory
IgA can cross-link large antigens with multiple epitopes.
 Secretory IgA protects the newborns against infection during the first month of life. Because the
immune system of infants is not fully functional, breastfeeding plays an important role in maintaining
the health of newborns.
 Secretory IgA has shown to provide an important line of defence against bacteria and viruses.
IgM

16. IgM constitutes about 5–8% of total serum immunoglobulins. It is a heavy molecule with a molecular weight
varying from 900,000 to 1,000,000 Da. It has a half-life of 5 days. IgM antibodies are short-lived and disappear
early as compared to IgG. The presence of IgM antibody in serum, therefore, indicates recent infection.
IgM is the main immunoglobulin that produces early in the primary response. It is present as a monomer on
the surface of virtually all B cells while in serum, it is present as a pentamer, composed of five
immunoglobulin subunits and one molecule of J chain. Comparatively, it is more efficient than IgG in
activating complement.
Because the pentamer has 10 antigen-binding sites, it is the most efficient immunoglobulin in agglutination,
complement fixation (activation), and other antibody reactions.
Functions
 IgM confers protection against invasion of blood by microbial pathogens. Deficiency of IgM
antibodies is associated with septicemia.
 IgM is not transported across the placenta; hence, the presence of IgM in the fetus or newborn
indicates intrauterine infection. The detection of IgM antibodies in serum, therefore, is useful for the
diagnosis of congenital infections, such as syphilis, rubella, toxoplasmosis, etc.




IgD
IgD comprises less than 1% of serum immunoglobulins. It is a monomer with a molecular weight of 180,000
Da. The half-life of IgD is only 2–3 days. it is present on the surface of many B lymphocytes and in small
amounts in serum. Both IgD and IgM serve as recognition receptors for antigens. The role of IgD in immunity
continues to remain elusive.
Functions
 it initiates immune responses. However, its exact function is not known.
IgE
IgE constitutes less than 1% of the total immunoglobulin pool. It has a molecular weight of 1,90,000 Da and
half-life of 2–3 days. Unlike other immunoglobulins that are heat stable, IgE is a heat-labile protein and it
easily inactivate at 56°C in 1 hour.
It is present in serum in a very low concentration(0.002%). It is mostly present in the lining of the respiratory
and intestinal tracts. Although, IgE is present in trace amounts in normal serum, persons with allergic
reactivity have greatly increased amounts of IgE and it may appear in external secretions.
Moreover, IgE does not fix complement and does not cross the placenta.

17. Functions
 it mediates immediate (anaphylactic) hypersensitivity ( to know more about hypersensitivity, click on
this link )
 it participates in host defenses against certain parasites.


T cell
1. Maturation
 The cells that enter the thymus encounter the thymic epithelium before progressing to the early
thymic progenitor cells (ETP). The cells at this stage are CD4-, CD8-, CD44+ CD25- and ckit+ cells.
 The microenvironment in the thymus restricts the potential of these cells to convert into myeloid
and DC cells.
 The thymus consists of four major compartments, where each of them performs a distinct
function and regulates different stages of T cell development.
 The compartments are the subcapsular zone, the cortex, the medulla, and the corticomedullary
junction.
 The development of the thymocyte progresses through different stages in different regions of the
thymus and can be traced by the alterations in the cell-surface marker expression of the
molecules.
 The double negative (DN) cells can be further classified into four different stages and are
identified by their lack of receptors.

18.  The DN1 cells are ETPs that exhibit high levels of CD117 and account for about 0.01% of the total
thymic T cell pool. The DN1 cells move from the corticomedullary junction into the deeper cortex
towards the subcapsular region.
 Here, the cells differentiate into DN2 thymocytes, including CD24+, CD25+, CD44+, and CD117+
cells. The DN2 thymocytes then experience a rearrangement of genes and the secretion of
cytokines like IL-7.
 The cells further differentiate into the DN3 stage, where the T cells expressed an invariant α-chain
called pre-Tα. The arrangement of genes together with the invariant chain produces signals to
proceed with the process of T cell maturation.
 At the DN3 stage, the cells mature into DN4, which is further upregulated into CD4 and CD8 cells
achieving a double positive status in the maturation process.
 The specificity and binding strength of the αβ T cell receptor determine the survival and
differentiation of the cells.
 The process is followed by two distinct processes; positive selection and negative selection.
a. Positive Selection
 Positive selection is the process of movement of double-positive T cells (CD4+ and CD8+) to the
cortex, where they encounter self-antigens.
 The thymic cortal epithelial cells express self-antigens on MHC molecules where the T cells
interact with the molecules. The cells that do not interact with the molecules strongly enough due
whereas others with high affinity to MHC cells survive.
 A large portion of the developing thymocyte due during the process, which lasts for a number of
days.
 In the positive selection, the CD4+ cells interact well with class MHC molecules, whereas the
CD8+ cells interact well with class II MHC molecules.
b. Negative Selection
 The cells that survive the positive selection move into the medulla and undergo negative
selection, which eliminates thymocytes with a high affinity for self-antigens.
 The cells that interact too strongly with the self-antigens receive an apoptotic signal resulting in
cell death.
 During the same process, however, some cells are selected to form Treg cells. The cells that
successfully complete the selection process exit the thymus as mature naïve T cells.
2. Activation
 The mature naïve T cells leave the thymus and reach the bloodstream, where they circulate until
they recognize their specific antigens on the surface of antigen-presenting cells.
 The activation of CD4+ cells occurs as a result of interaction between the T-cell receptor and a co-
stimulatory molecule (CD28 or ICOS) present on the T cell.
 The activation of CD4+ cells is essential for the initial antigenic activation of naïve CD8 T cells and
memory T cells.
 The initial signal is provided by the binding of the T cell receptor to the cognate peptide present
on the class II MHC. A similar peptide is present on the class II MHC which activates the
CD8+ cells.
 The second signal is provided as a result of co-stimulation, where the surface receptors are
induced by a relatively small number of stimuli which are products of pathogens or breakdown
products of cells.
 Naïve T cells only express the CD28 as a co-stimulatory receptor that interacts with CD80 and
CD86 proteins present on APCs.

19.  The two-step activation process prevents inappropriate responses to self-antigens as self-
peptides do not provide suitable co-stimulation.
 After the two signals, T cells also receive stimulation in the form of cytokines. The cytokine signal
determines the fate of T cells, especially in the case of helper T cells.
B cell
1. Maturation of B cell
 Maturation is the first step of B cell development within the bone marrow before traveling to
other lymphoid organs like the spleen and lymph nodes.
 The development of immature B cells in the bone marrow can be described into different stages,
each of which is characterized by various gene expression patterns and immunoglobulin H chain
and L chain gene arrangements.
 During the development, B cells generate various B cell receptors as a part of the selection
process.
 The selection occurs via one of two mechanisms; positive mechanisms occur via antigen-
independent signaling where if the receptors on the B cells do not bind to their ligands, the cells
do not receive proper signals and cease to develop.
 A negative selection mechanism occurs by the binding of self-antigen to the BCR, where if the
BCR can bind strongly to a self-antigen, the development of B cells is ceased.
 In order to complete development, immature B cells migrate from the bone marrow into the
spleen as transitional B cells through the two stages; T1 and T2.
 The cells are considered T1 B cells through their migration to the spleen and after entry into the
spleen. In the spleen, the T1 B cells mature into T2 B cells.
 The T2 B cells differentiate either into follicular B cells or marginal zone B cells depending on the
signals received by the receptors on the cells.
 The cells are considered mature B cells or naïve B cells after differentiation in the spleen.
2. Activation of B cell
 B cell activation usually occurs in the spleen or other secondary lymphoid organs like lymph
nodes.
 After maturation in the bone marrow, the cells migrate to lymphoid organs as they tend to have a
constant supply of antigen with the help of the circulating lymph. The migration is induced by
chemokine interaction between CXCL13 and CXCR5.
 The activation of B cells begins with exposure to antigen via different receptors present on the
surface like the BCR receptors.
 The response of B cells upon detection of antigen depends on the structure of the antigens.
a. T cell-dependent B cell response
 At the beginning of the T-dependent B cell response, the B cells bind to the antigen via the Ig
receptors. Some of the antigens are internalized into specialized vesicles within the B cells.
 The internalized antigens are processed and re-expressed in the form of peptides presented in the
antigen-binding groove of class II MHC molecules.
 The T cells that have been previously exposed to antigen-bearing dendritic cells can now bind to
the MHC-presented peptide on the surface of the B cell.
 The binding is further enhanced by the interaction of accessory molecules on the T- and B-cell
surfaces.
 Some of the T-cell-activated B cells now move into specialized regions of the lymph node or
spleen to begin the process of differentiation.

20. b. T cell-independent B cell response
 Activation of B cells can also occur without the participation of T cells, and it produces a
particular subset of B cells that respond with antibody production to particular classes of
antigens.
 Antigens that elicit a T cell-independent antibody response tend to be polyvalent with repeating
determinants shared among many microbial species. These antigens are called Tl antigens.
 The responses to these antigens are usually rapid even though antibodies generated by this
method have lower affinity and are less functionally versatile than those activated by T cell-
dependent methods.
 Like in the case of T cell-dependent activation, B cells activated by Tl antigens also require
additional signals to attain complete activation.
 However, these cells receive the signals either by recognition and binding a microbial constituent
to toll-like receptors or by extensive cross-linking of the B cell receptor epitopes to the bacterial
or viral surfaces.
 The B cells activated by the T cell-independent method proliferate outside the lymphoid centers
and undergo immunoglobulin class switching and differentiation.
3. Differentiation of B cell
 The differentiation of activated B cells is stimulated by the interaction of the B cell receptors to
specific antigens.
 Some activated cells are moved into regions at the border of the T cell and B cell areas known as
primary foci.
 At the primary foci, the cells undergo differentiation into plasma cells in about four days post-
stimulation.
 The differentiation cells then migrate to the medullary cord regions of the node, where they
secrete large quantities of antibodies.
 Post differentiation, some of the plasma cells die after the primary response, whereas others
remain in the bone marrow or the gut as long-lived plasma cells.
 Some antigen-stimulated B cells, however, do not enter the primary foci but rather migrate to
follicles on the lymph nodes or the spleen.
 As the B cells begin to differentiate, the follicles swell with antigen-specific lymphocytes,
resulting in a germinal center’s appearance.
 At the end of the immune response, memory B cells remain that are the daughter cells of the cells

21.  stimulated during th e
response.


B cell (B lymphocyte) Applications
The applications or functions of B cells can be explained in threefold;
1. Antigen Presentation
 Even though the primary function of B cells is an antibody-mediated immune response, these
cells also function as professional antigen-presenting cells.
 B cells have antigen-MHC complexes as well as T cell receptors involved in T-cell activation.
 B cell lymphocytes have also been associated with the inactivation of T cells in the case of the
non-specific immune system or innate immune system.
2. Cytokine Secretion
 B lymphocytes are also known to produce cytokines which are essential for cell-cell
communication, especially during an immune response.
 The cytokine production invites white blood cells to induce phagocytosis on antigens attached to
the B cell antibodies.
3. Antibody production
 Antibody production is the most important function of B cells as these are involved in the
antibody-mediated humoral immune response.
 The antibodies fight against multiple antigens of different origins to protect the body against
possible harm.
4. B cell-based immunotherapy
 Besides being the producers of antibodies, B cells also contribute to immune regulation via
cytokine production and antigen presentation.
 The use of B cells as APCs has increased over the years as these can be consistently generated
from peripheral blood and are relatively insensitive towards tumor-derived immunosuppressive
mechanisms.
 These also do not induce tolerance by themselves and are well tolerated in terms of toxic side
effects.

22. 3. Differentiation
 The differentiation of T cells into different types of T cells usually occurs in the form of lineage
commitment which is based on the affinity of the T-cell receptor towards self-antigen.
 The decision is to be made during the double-positive thymocyte stage, where the cells determine
whether to join the CD8+ cytotoxic T cells or the CD4+ helper T-cell.
 The lineage commitment requires changes in genomic organization and gene expression that
results in the silencing of the gene and the expression of a gene associated with a particular
lineage function.
 The exact mode of differentiation is not yet clearly understood, but the most recent model that
explains the lineage indicates that it is based on the affinity for one of the two MHC classes.

Macrophages: Structure, Immunity, Types, Functions
April 29, 2023 by Anupama Sapkota
Edited By: Sagar Aryal
Macrophages are mononuclear cells functioning as professional phagocytes to remove dying, dead
or harmful pathogens.
Macrophages are a type of white blood cell of the immune system where they engulf and digest
particles that are detected as antigens by other blood cells.
 These are larger phagocytic cells that occur in essentially all types of tissues, and their structure
and shape depend on the stage of maturation of the cells.
 Macrophages found in different organs have different names like the macrophages of lungs are
called alveolar macrophages, while those in the liver are called Kupffer cells.
 Even though phagocytosis is the primary function of macrophages, these also play an essential
role in nonspecific defense as well as in adaptive immunity.
 Macrophages are important blood cells that have important roles in almost all aspects of an
organism’s biology as different subsets of macrophages are involved in different functions in the
body.
 Macrophages in the body are produced by the differentiation of monocytes in tissues that can
then be identified by flow cytometry or immunohistochemical staining.
 Macrophages keep flowing through the blood where they migrate to and circulate within all
tissues, patrolling for pathogens or eliminating dead cells and debris.

23.  Macrophages consist of a specialized group of receptors called Toll-like receptors that recognize
products of bacteria and other microorganisms.
Macrophages. Created with BioRender.com
Structure of Macrophages
 The morphology of macrophages depends on the various state of activity of the cells. The size of
the cells ranges between 10-30 µm in diameter.
 The cytoplasm of a macrophage contains vacuoles and granules that are basophilic in nature. The
nucleus is ovoid and measures about 6-12 µm in diameter.
 In a phase-contrast microscope, peritoneal macrophages contain light gray diffuse cytoplasm
with dark gray rod-shaped mitochondria.
 The periphery of the cytoplasm contains finely granular and lacks structures like endoplasmic
reticula and attached ribosomes.
 Three different types of vesicles are visible in the cytoplasm in the form of pinocytic vesicles with
various sized organelles contained a diner granular material.
 Ribosomes can be observed attached to the external portion of the nuclear membrane that is
continuous with the endoplasmic reticula.
 The dense granules in the cytoplasm are mostly secondary lysosomes that are derived from
endocytic vacuoles.
 In the case of inflammatory macrophages, slim cytoplasmic extensions are observed that remain
tightly intertwined with adjacent epithelioid cells.
 Some observations might even indicate giant cells of granuloma as a result of the fusion of
preexisting macrophages.
1.8M
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How do Macrophages work against pathogens? (Immunity)
The primary role of macrophages is homeostasis, where the cells protect the host against foreign
invaders and clears necrotic and apoptotic debris post-injury. Macrophages perform these functions
by four distinct mechanisms; sensing, chemotaxis, phagocytosis and repair, and adaptive
stimulation.
1. Sensing
 Many macrophages remain in the bloodstream as patrolling cells. These macrophages use
different intracellular and cell-surface pattern recognition receptors (PRRs) to sense their local
environment.
 When these receptors detect appropriate particles, they generate signals that detect the
macrophage response.

24.  The innate receptors of macrophages can recognize molecular patterns that can detect such
patterns across a number of species.
 The sensing groups detected by macrophages can be categorized into two groups; pathogen and
danger signals and modified host proteins and cellular debris.
 The Toll-like Receptors (TLR) family of receptors is the most predominant pathogen sensing
group of molecules with 14 members.
 In addition to the detection of antigens, these receptors also induce inflammatory signaling by
the expression of cytokines like IL-6, TNF-α, and IL-2.
 Macrophages also express cell-surface Fc receptors like Fc gamma and Fc epsilon. These receptors
bind to antibodies that are already bound to antigens, resulting in phagocytosis.
2. Chemotaxis
 After the sensing of an antigen, macrophages stimulate the expansion of activated T cells and the
secretion of chemokines to recruit other effector cells, resulting in neutralization and clearance.
 Some of the common chemokines released by activated macrophages are CCL-3, CCL-4, CCL-5,
CXCL-9, etc.
 Other chemokines like CCL-17 and CCL-22 attract Th2 lymphocytes and natural killer cells along
with eosinophils and basophils.
TH1 Cells Help
Macrophages Kill Intracellular Bacteria
3. Phagocytosis and Tissue repair
 The most important mechanism of immune response by macrophages is phagocytosis for the
clearance of damaged and cell debris.
 Macrophages begin to engulf unwanted materials with the help of cell-surface receptors that can
identify their targets.
 The materials are sequestered into compartments that fuse with a lysosomal compartment
containing a number of highly reactive and toxic molecules.
 Some of the common compounds involved in the destruction of the phagosomal contents are
ROS and NO. Nitric acid regulates the level of ROS to produce toxic reactive nitrogen species.
 The returning of host tissues into the homeostatic state requires the repair and remodeling of the
local environment. The activated macrophages are responsible for tasks like promoting
extracellular matrix remodeling, cell growth, angiogenesis, and collagen production.

25. 4. Adaptive Stimulation
 Adaptive stimulation of T lymphocytes is also a mechanism of immune response of macrophages
as these cells provide a means to generate antigenic peptide sequences.
 These peptides are presented to T cells to bind to the cell-surface MHC class II receptors.
 The stimulation of macrophages, when coupled with additional signaling of IL-12 or IL-4, will lead
to the expansion of antigen-specific T lymphocytes.
 However, the adaptive stimulation of macrophages is more limited than other innate immune
cells like dendritic cells, as these can only stimulate the expansion of activated T lymphocytes.
Figure: Phagocytosis.
Image created with biorender.com
Types of Macrophages
Macrophages can be classified into one of the two opposing phenotypes; classically activated or M1
macrophages and alternatively activated or M2 macrophages. Macrophages are also of different
types depending on the type of tissue they are found on. The classification is based on the activation
phenotype of recruited macrophages which, in turn, depends on the surrounding
microenvironment.
1. Classically activated macrophages or M1 macrophages
 Macrophages stimulated with a toll-like receptor in the presence of interferon-γ result in the
formation of M1 macrophages.
 These macrophages have an enhanced capacity to present antigen, produce nitric oxide and
secrete a large number of chemokines,
 These macrophages are essential in defense against bacteria which can be damaging to the host
as a result of collateral damage brought about by the defense mechanisms they utilize.
2. Alternatively-activated macrophages or M2 macrophages
 Macrophages activated as a result of exposure to IL-4, IL-3 produced by CD4+ T cells from the
alternatively activated macrophages or M2 macrophages.
 These macrophages are usually produced in the response to parasites and fungi. These express
high amounts of cytosolic arginase and extracellular matrix-related proteins.
 M2 macrophages have the ability to limit inflammation and also play an essential role in tissue
repair and wound healing.

26. Macrophage Subtypes in
Atherosclerosis
Functions of Macrophages
The following are some of the functions of macrophages;
1. Macrophages are phagocytes involved in the removal of dead cells and cellular debris as a part of
homeostasis. Phagocytosis is one of the principal mechanisms involved in innate immunity.
2. Macrophages also present antigens to other immune cells as a part of initiating an immune
response. These also secrete different chemokines and a wide variety of powerful substances that
influence the activation of cells of adaptive immunity.
3. Macrophages are also involved muscle repair, growth, and regeneration after the inflammation of
different sites.
4. M2 macrophages are also called wound healing macrophages as these limit the extent of the
inflammation and allow tissue repair and regeneration.
5. Since macrophages are scavengers, they continuously remove dead erythrocytes from blood. The
process results in the storage of iron released during the process in the form of ferritin, thus
playing a role in iron homeostasis.


Major Histocompatibility Complex I- Structure, Mechanism,
Functions
June 10, 2022 by Sagar Aryal
Edited By: Sagar Aryal
 Major Histocompatibility Complex (MHC) is a part of the genome of all vertebrates that code for
molecules which are important in immune recognition.
 In humans, the MHC is a cluster of genes located on chromosome 6 which code for MHC proteins
also called Human Leukocyte Antigen (HLA).
 MHC proteins are a set of cell surface proteins essential for the acquired immune system to
recognize foreign molecules which in turn determines histocompatibility.
 The main function of MHC molecules is to bind to peptide antigens and display them on the cell
surface for recognition by appropriate T-cells.

27.  Among the many genes in the human MHC, those that encode the class I, class II, and class III
MHC proteins are considered important.

 MHC class I proteins are encoded by the HLA-A, HLA-B, and HLA-C genes encoding HLA-A, HLA-
B, and HLA-C molecules respectively.
 Class I molecules are found on virtually all nucleated cells in the body including platelets. Key
exceptions are observed on cells in the retina and brain and the non- nucleated red blood cells.
 They are recognized by CD8 co-receptors through the MHC Class I β2 subunit.
 These MHC Class I molecules sample peptides generated within the cell and signal the cell’s
physiological state to effector cells of the immune system, particularly CD8+ T lymphocyte.
Table of Contents

 Structure of Major Histocompatibility Complex I
 Mechanism of Major Histocompatibility Complex I
 Antigen Processing and Presentation
 Transplant Rejection
 Reference
 Major Histocompatibility Complex I- Structure, Mechanism and Functions
Structure of Major Histocompatibility Complex I

 Class-I MHC is a glycoprotein molecule containing a 45KDa α-chain associated non-covalentely
with a 12KDa β2 microglobulin molecule.
 The α chain composed of three domains—α1, α2, and α3.
 The α1 rests upon β2 microglobulin while the α3 domain is transmembrane anchoring the MHC
class I molecule to the cell membrane.

28.  The peptide-binding groove present in the central region of the α1/α2 heterodimer helds the
peptide being presented.
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Mechanism of Major Histocompatibility Complex I
 MHC class I glycoproteins present antigens of endogenous origin to TCRs of CD8+ T cells.
 Endogenous peptides derive from degradation of intracellular proteins, including viral or tumor
antigens in infected or transformed cells, through the proteasome.
 Degradation products translocate from the cytoplasm to the endoplasmatic reticulum (ER) where
they are loaded on MHC class I molecules via the peptide-loading complex that includes the ER
transporter associated with antigen processing (TAP1/2), tapasin, the oxidoreductase ERp57, and
the chaperone protein calreticulin.
 Cellular components involved in the presentation of endogenous antigens, from proteasome
subunits to the peptide-loading complex, are collectively referred to as antigen-processing
machinery (APM).
 CD8+ T lymphocytes express CD8 receptors, in addition to the T-cell receptors (TCR).
 When a Cytotoxic T cell CD8 receptor docks to a MHC class I molecule and the TCR fits the
epitope within the MHC class I molecule, the CD8+ T lymphocytes triggers the cell to undergo
programmed cell death by apoptosis.
 This helps mediate cellular immunity which is the primary means to address intracellular
pathogens, such as viruses and some bacteria.
Functions of Major Histocompatibility Complex I
1. Antigen Processing and Presentation
Nucleated cell normally present peptides, mostly self peptides derived from protein turnover and
defective ribosomal products. Also, during viral infection, intracellular microorganism infection, or
cancerous transformation, such proteins degraded inside the cell by proteasomes are also loaded
onto MHC class I molecules and displayed on the cell surface.
2. Transplant Rejection
During transplant of an organ or stem cells, MHC molecules themselves act as antigens and can
provoke immune response in the recipient causing transplant rejection. Since, the MHC variation in
the human population is high and no two individuals except identical twins express the same MHC
molecules, they can mediate transplant rejection.

Major Histocompatibility Complex II- Structure, Mechanism and
Functions
June 12, 2022 by Sagar Aryal
Edited By: Sagar Aryal
 Major Histocompatibility Complex (MHC) is a part of the genome of all vertebrates that code for
molecules which are important in immune recognition.
 In humans, the MHC is a cluster of genes located on chromosome 6 which code for MHC proteins
also called Human Leukocyte Antigen (HLA).
 MHC proteins are a set of cell surface proteins essential for the acquired immune system to
recognize foreign molecules which in turn determines histocompatibility.

29.  The main function of MHC molecules is to bind to peptide antigens and display them on the cell
surface for recognition by appropriate T-cells.
 Among the many genes in the human MHC, those that encode the class I, class II, and class III
MHC proteins are considered important.

 MHC class II molecules are a class of major histocompatibility complex (MHC) molecules normally
found only on antigen-presenting cells which are important in initiating immune responses.
 MHC Class II proteins are encoded by the genes of HLA-D region of the genome in humans.
 Unlike class I proteins, they have a restricted tissue distribution and are chiefly found on
macrophages, dendritic cells, B cells, and other Antigen Presenting Cells (APCs) only.
 However, their expression on other cells (eg, endothelial cells or epithelial cells) is induced by
IFN-γ.
 The antigens presented by class II peptides are derived from extracellular proteins and not
endogenous antigens as in MHC class I.
 Class II MHC molecules have β1 and β2 subunits and thus can be recognized by CD4 co-receptors.
 These MHC Class II molecules sample extracellular peptides mainly extracellular pathogens and
by interacting with immune cells like the T helper cell (TCD4+) regulate how T cells respond to an
infection.
Table of Contents

Structure of Major Histocompatibility Complex II

30.  MHC-II molecules are dimers consisting of a 133 KDa α-chain and 28KDa β-chain which are
associated by non-covalent interactions.
 Both the α-chain and β-chain are made up of two domains – α1 and α2 and β1 and β2
respectively.
 They are membrane bound glycoprotein that contains external domains, a transmembrane
segment and a cytoplasmic tail.
 An open ended groove formed between α-chain and β-chain at the proximal end serves as the
peptide biding cleft which can bind antigenic peptide.
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Mechanism of Major Histocompatibility Complex II
 MHC class II molecules present antigens of exogenous origin to CD4+ T cells.
 Phagocytes such as macrophages and immature dendritic cells take up entities
by phagocytosis into phagosomes which fuse with lysosomes and the acidic enzymes cleave the
uptaken protein into many different peptides.
 During synthesis of class II MHC, the molecules are transported from the endoplasmic reticulum
(ER) via the Golgi to endosomal compartments. The α and β chains produced are complexed with
a special polypeptide known as the invariant chain (Ii). The Ii prevents endogenous peptides from
binding to the groove of MHC class II molecules.
 After removal of Ii in the acidic endosomal compartments, peptides are able to bind to the MHC
groove.
 A particular peptide exhibiting immunodominance loads onto MHC class II molecules.
 Peptide-loaded MHC class II molecules are then transported to the membrane surface for antigen
presentation.
 The peptide:MHC class II complex is then recognized by the cognate T cell receptor (TCR) of
helper T cells.
Functions of Major Histocompatibility Complex II
 The TCR–peptide: MHC class II engagement is crucial to the induction and regulation of adaptive
immunity by selecting the mature CD4+ T cell repertoire in the thymus and activating these
lymphocytes in the periphery.
 The secure attachment to the MHC molecule with the presented peptide ensure stable peptide
binding which enhance T cell recognition of the antigen, T cell recruitment, and a proper immune
response.
 Since they sample and present antigens from exogenous sources, MHC class II molecules are
critical for the initiation of the antigen-specific immune response.