AUTOIMMUNITY & HYPERSENSITIVITY REACTIONS (4).pdf

Immunology lecture notes

1. AUTOIMMUNITY &
HYPERSENSITIVITY REACTIONS

2. AUTOIMMUNITY

3. •This occurs when the immune system attacks self-molecules as a result of a breakdown
of immunologic tolerance to autoreactive immune cells.
•Many autoimmune disorders have been strongly associated with genetic, infectious,
and/or environmental predisposing factors.
•Comprising multiple disorders and symptoms ranging from organ-specific to systemic,
autoimmune diseases include;
•Insulin-dependent diabetes mellitus,
•Rheumatoid arthritis (RA),
•Systemic lupus erythematosus (SLE),
•Scleroderma,
•Thyroiditis, and
•Multiple sclerosis (MS).
•There are also implications of autoimmune pathology in such common health problems
as;
•arteriosclerosis,
•inflammatory bowel disease,
•schizophrenia, and
•certain types of infertility.

4. •Autoimmune reactions also reflect an imbalance between effector and
regulatory immune responses, typically developing through stages;
•Initiation and propagation, and
•Frequent phases of resolution (indicated by clinical remissions) and
•Exacerbations (indicated by symptomatic flares).
•Internationally, it is now estimated that cases of autoimmune diseases are
rising by between 3% and 9% a year, with this increased associated with the
western diet.
•Autoimmune diseases are also more common in women, suggesting a
hormonal or sex-linked influence.
•Collectively, 75% of autoimmune disease is found in women and most
commonly arises during the childbearing years.
•The most striking gender bias is seen in SLE where, during this time of their life,
women are approximately 10 times more likely to develop this disease than
men. However, this drops to only a 2.5‐fold excess following the menopause.

5. •There is a suggestion that higher oestrogen levels are found in patients
compared with controls.
•In glomerulonephritis, knocking out the oestrogen receptor α chain in the NZB
× NZW mouse model lowers autoantibody levels, decreases the severity of
glomerulonephritis, and increases survival.
•Pregnancy is often associated with amelioration/improvement of autoimmune
disease severity.
•For example in rheumatoid arthritis (RA), and there is sometimes a striking
relapse after giving birth, a time at which there are drastic changes in
hormones such as prolactin, not forgetting the loss of the placenta.
•Autoimmune attacks follow a variety of routes:
•Circulating antibodies bind to cells and either assist in destroying them or interfere with
their functions.
•Antibody-antigen combinations circulate in the blood and lymph systems, lodge in
various tissues, and cause cell destruction.
•Cell-killing lymphocytes launch a direct attack on healthy tissues.

7. •Autoimmune diseases can be either organ-specific or systemic.
•In organ-specific autoimmunity, an immune response is directed toward
antigens in a single organ.
•Examples are;
•Addison disease, in which autoantibodies attack the adrenal cortex, and
•myasthenia gravis, in which they attack neuromuscular cells.
•In systemic autoimmunity the immune system attacks self antigens in several
organs.
•For example, systemic lupus erythematosus (SLE), is characterized by
inflammation of the skin, joints, and kidneys, among other organs.
•Because the cause of immune system failure is unknown, treatment of
autoimmune diseases centres on alleviating symptoms such as inflammation.
•Current therapies, such as cytokine antagonists, have shown great promise in
treating many of these diseases.

8. •TNF-α antagonists have changed the course of rheumatoid arthritis, and other
cytokine antagonists are showing impressive efficacy in various other diseases.
•In organ-specific disorders, attempts are made to correct the specific defect.
•Drugs that suppress the production of antibodies must be used carefully to
avoid lowering the body’s resistance to infection.
•In most cases, this necessitates continued and sometimes life-long therapy,
resulting in an increased risk of malignant and infectious complications.
•Tackling these diseases at their source will require an understanding of how
the abnormal immune reactions arise, how they are sustained, and the
intrinsic mechanisms used to suppress these responses in healthy individuals.
•Augmenting regulatory mechanisms and establishing robust and long-lived
disease resolution is a goal of new therapeutic strategies.

9. •Autoimmune diseases, like
many other complex disorders,
are believed to arise from a
combination of genetic and
environmental factors.
•One hypothesis on their origin
is that polymorphisms in
various genes result in
defective regulation, or
reduced threshold for
lymphocyte activation,
additionally, environmental
factors initiate or augment
activation of self-reactive
lymphocytes that have escaped
control, and are poised to react
against self-constituents.
GENETIC SUSCEPTIBILITY, ENVIRONMENTAL STIMULI, AND DEFECTIVE
REGULATION ARE RESPONSIBLE FOR INITIATING AUTOIMMUNITY.

10. •Genetic polymorphisms in immune-related genes (including HLA (MHC),
cytokines/receptors, and those involved in central tolerance) may lower the
threshold for the activation of autoreactive T cells.
•Environmental triggers such as infection, the microbiome, and tissue injury
generate a proinflammatory environment that supports the activation of
autoreactive lymphocytes.
•Tregs normally function to suppress autoreactive T cells, but defects in
development, stability, or function may render these cells dysfunctional and
unable to control autoreactive T cell responses.
•Alone or in combination, these factors can contribute to the escape, activation,
and proliferation of autoreactive lymphocytes that result in tissue injury and
clinical disease.
•Numerous genetic polymorphisms have been tied to different autoimmune
diseases.

11. •The contribution of each gene to a particular disease, as indicated by the odds
ratio, is small, and it is likely that multiple polymorphisms contribute to disease
development in individual patients.
•However, it has proved difficult to define the role of most of these
polymorphisms in the breakdown of tolerance to self-antigens and the
development of autoimmunity.
•For instance, of all the genes associated with autoimmune diseases, the
strongest associations, and the ones that have been known for the longest
time, are with particular HLA alleles.
•Cytokine and cytokine receptor genetic polymorphisms have been linked to
many different autoimmune diseases.
•Perhaps the best example of this is IL23R, which codes for IL-23, a cytokine
that augments the proinflammatory capacity of Th17 cells.
•Genetic polymorphisms in IL23R have been discovered in ankylosing
spondylitis, Behçet’s disease, Crohn’s disease, psoriasis, and ulcerative colitis

12. •Accordingly, inflammatory Th17 cells have been associated with tissue damage
in all of these diseases, and targeting these pathways with monoclonal
antibodies specific for either p40 (a subunit of IL-23) or IL-17A has shown
efficacy in almost all of these disorders.
•Infections have long been suspected to trigger autoimmune reactions.
•Multiple theories have been proposed to explain this association, including
epitope spreading, antigenic complementarity, and excessive innate/pattern
recognition receptor activation.
•For example, evidence of Epstein-Barr virus (EBV) infection in post-mortem
brain tissue has been associated with multiple sclerosis (MS) but not other
inflammatory disorders.
•Additionally, systemic infections have been reported to trigger relapses in
patients with relapsing-remitting MS through enhancement of myelin-specific T
cell responses.

13. •Another example of the association of infections with autoimmunity is that of
periodontal infections and rheumatoid arthritis.
•In contrast, infections are also postulated to protect against some autoimmune
diseases.
•For example, infection of germ-free mice with Bacteroides fragilis has been
reported to protect against experimental autoimmune encephalomyelitis, the
mouse model of MS, through induction of Treg cells.
•Additionally, a higher incidence of MS and type 1 diabetes is correlated with a
decreased number of infections in western countries.
•Recent interest has focused on the possible role of the microbiome in
influencing local and systemic immune responses.
•Much of the emphasis has been on the gut microbiome.
•It is now believed that inflammatory bowel disease (IBD) is initiated by
dysregulated and exaggerated immune responses to intestinal commensal
microbes.

14. •The major manifestations of IBD may be caused by antimicrobial immune
reactions and not by true autoimmunity (i.e., directed at tissue self-antigens).
•There are also several studies in mice that implicate commensal microbes in
autoimmune disease, including type 1 diabetes.
•A well-recognized nonmicrobial environmental trigger is UV irradiation for
cutaneous lupus.
•A possible explanation for this connection is that UV radiation induces
apoptotic death of many cell types and increases the burden of nuclear
antigens, especially if the dead cells cannot be efficiently cleared.
•It has been suggested that low-level natural cell death in tissues is a
mechanism for maintaining peripheral tolerance to tissue antigens through
tolerance-promoting dendritic cell populations.
•It is plausible that lupus patients have a genetic predisposition for this system
to become easily overwhelmed and are thus unable to maintain tolerance in
the presence of continual UV exposure.

15. •Most patients present with clinical disease during the propagation phase,
which is characterized by progressive inflammation and tissue damage.
•The self-perpetuating nature of autoimmune diseases can explain why these
conditions reach the propagation phase.
•First, the self-antigens that drive the reaction cannot be eliminated.
•This is compounded by the emergence of new antigenic epitopes as a result of
tissue damage and alterations in self-proteins, the phenomenon known as
epitope spreading.
•Epitope spreading sets up a vicious cycle in which newly created antigenic
epitopes activate more lymphocytes of different specificities, recruiting these
cells into the reaction, leading to more tissue damage and the emergence of
even more novel epitopes targeted by autoreactive lymphocytes.
•Second, the autoimmune reaction creates an inflammatory environment in
which multiple immune cells interact to produce cytokines and other
mediators that amplify the reaction, creating a catastrophic inflammatory loop.

16. •Consistent with this notion is the finding that type I interferons, a product of
plasmacytoid dendritic cells that is produced during inflammatory reactions, is
a biomarker for the progression of SLE and may be involved in the propagation
of this disease.
•The best evidence of the dominant drivers of disease propagation in humans is
clinical data showing that targeting of specific cytokines can result in a
complete amelioration of the propagation phase of disease.
•Thirdly, and perhaps most importantly, the propagation of autoimmunity may
be related to the progressively increasing ratio of effector to regulatory cells.
•Once a pathologic immune reaction starts, there is increasing accumulation of
effector T cells in the tissues that are the main drivers of the autoimmune
reaction.
•This may be accompanied by a relative decline in Treg number, or increased
numbers of dysfunctional Tregs.

17. •Paradoxically, the inflamed skin of patients with psoriasis has increased
numbers of Tregs; however, these cells appear to function abnormally, in that
they are capable of producing increased amounts of IL-17.
•Therapeutic strategies to reset the effector T cell/Treg balance are an exciting
new approach to treat autoimmune disease.
•Low-dose IL-2 therapy is thought to preferentially augment Treg numbers
and/or function and has been shown to be of clinical benefit in patients with
chronic graft-versus-host disease (GVHD), autoimmune vasculitis, and alopecia
areata.
•Additionally, adoptive transfer of large numbers of ex vivo expanded Tregs has
been shown to be efficacious in preventing acute GVHD and is currently being
tested for the treatment of type 1 diabetes.

18. HYPERSENSITIVITY REACTIONS

19. •Hypersensitivity refers to excessive, undesirable (damaging, discomfort-
producing and sometimes fatal) reactions produced by the normal immune
system to either endogenous or exogenous pathogens
• Hypersensitivity reactions require a pre-sensitized (immune) state of the host.
•These reactions can be divided into four types based on the mechanisms
involved and time taken for the reaction:
•Type I,
•Type II,
•Type III and
•Type IV.
•Frequently, a particular clinical condition (disease) may involve more than one
type of reaction.
•They type I reaction is central to the group of disorders termed “allergic” while
type II, III and IV describe a disease mechanism, but do not usefully describe a
discrete group of disorders.

20. •Type I Hypersensitivity
•This is also known as immediate or anaphylactic hypersensitivity.
•The reaction may involve;
•Skin (urticaria and eczema),
•Eyes (conjunctivitis),
•Nasopharynx (rhinorrhoea, rhinitis),
•Bronchopulmonary tissues (asthma) and
•Gastrointestinal tract (gastroenteritis).
•The reaction may cause a range of symptoms from minor inconvenience to
death.
•The reaction usually takes 15 - 30 minutes from the time of exposure to the
antigen, although sometimes it may have a delayed onset (10 - 12 hours).
•Immediate hypersensitivity is mediated by IgE.
•The primary cellular component in this hypersensitivity is the mast cell or
basophil.

21. TYPE I HYPERSENSITIVITY REACTION
IgE is typically bound to Fc receptors (FcR) on the surface of immune cells, such as mast cells and
basophils. Crosslinking of an allergen with the IgE signals the immune cells to degranulate,
releasing inflammatory mediators (e.g., histamine) that instantly trigger a hypersensitivity reaction.
The pathophysiology of type I hypersensitivity reactions (e.g., anaphylaxis, food allergies, drug
reactions), which can be severe enough to result in anaphylactic shock.

22. When the antigen
enters the body again,
it cross links
theIgEbound to the
sensitised cells,
causing the release of
preformed mediators
including histamine,
leukotrienes and
prostaglandins. This
leads to widespread
vasodilation,
bronchoconstriction,
and increased
permeability of
vascular endothelium.

23. •The reaction is amplified and/or modified by platelets, neutrophils and
eosinophils.
•A biopsy of the reaction site demonstrates mainly mast cells and eosinophils.
•The mechanism of reaction involves preferential production of IgE, in response
to certain antigens (allergens).
•The precise mechanism as to why some individuals are more prone to type-I
hypersensitivity is not clear.
•It has been shown, however, that such individuals preferentially produce more
of TH2 cells that secrete IL-4, IL-5 and IL-13, which in turn favour IgE class
switch.
•IgE has very high affinity for its receptor on mast cells and basophils, and upon
interaction with them, it causes their degranulation.
•The agents released from mast cells and their effects include histamine which
causes bronchoconstriction, mucus secretion, vasodilatation and increased
vascular permeability.

24. •Mast cells may be triggered by other stimuli such as:
•Exercise,
•Emotional stress,
•Chemicals (e.g., photographic developing medium, calcium ionophores, codeine, etc.),
•Anaphylatoxins (e.g., C4a, C3a, C5a, etc.).
•These reactions, mediated by agents without IgE-allergen interaction, are not
hypersensitivity reactions, although they produce the same symptoms.
•The reaction is amplified by PAF (platelet activation factor) which causes
platelet aggregation and release of histamine, heparin and vasoactive amines.
•Eosinophil chemotactic factor of anaphylaxis (ECF-A) and neutrophil
chemotactic factors attract eosinophils and neutrophils, respectively, which
release various hydrolytic enzymes that cause necrosis.
•Diagnostic tests for immediate hypersensitivity include skin (prick and
intradermal) tests, measurement of total IgE and specific IgE antibodies against
the suspected allergens.

25. •Total IgE and specific IgE antibodies are measured by a modification of enzyme
immunoassay (ELISA).
•Increased IgE levels are indicative of an atopic condition (a predisposition toward
developing certain allergic hypersensitivity reactions), although IgE may be elevated
in some non-atopic diseases (e.g., myelomas, helminthic infection, etc.)
•Symptomatic treatment is achieved with anti-histamines which block histamine
receptors.
•Cromolyn sodium inhibits mast cell degranulation.
•Late onset allergic symptoms, particularly bronchoconstriction which is mediated by
leukotrienes, are treated with leukotriene receptor blockers or inhibitors of the
cyclooxygenase pathway (Cox inhibitors; non steroidal anti-inflammatory drugs
(NSAIDs)).
•Symptomatic, although short term, relief from bronchoconstriction is provided by
bronchodilators (inhalants).
•The use of IgG antibodies against the Fc portions of IgE that binds to mast cells has
been approved for treatment of certain allergies, as it can block mast cell
sensitization.

26. •Hyposensitization (immunotherapy or desensitization) is another treatment
modality which is successful in a number of allergies, particularly to insect
venoms and, to some extent, pollens.
•This is a form of immunotherapy where the patient is “gradually vaccinated”
against progressively larger doses of the specific allergen.
•Hyposensitization can either reduce the severity or eliminate hypersensitivity
altogether.

27. •Type II Hypersensitivity
•Type II hypersensitivity is also known as cytotoxic hypersensitivity and may
affect a variety of organs and tissues.
•In this type of hypersensitivity reaction, antibodies target cell surface antigens.
•The antibodies are specific for (or able to cross-react with) "self" antigens.
•When these circulating antibodies react with a host cell surface, tissue damage
may result.
•The antigens are normally endogenous, although exogenous chemicals
(haptens) which can attach to cell membranes, can also lead to type II
hypersensitivity.
•The reaction time is minutes to hours.
•Type II hypersensitivity is primarily mediated by antibodies of the IgM or IgG
classes and complement.
•Phagocytes and NK cells may also play a role.

28. Type II cytotoxic reaction is
mediated by antibodies
directed against antigens on
the cell membrane that
activates complement
thereby causing antibody-
mediated destruction of
cells. The cell membrane is
damaged by a membrane
attack complex during
activation of the
complement

29. •Biopsies of the lesions that arise as a result of this reaction have shown that
they contain antibody, complement and neutrophils.
•Diagnostic tests include detection of circulating antibody against the tissues
involved and the presence of antibody and complement in the lesion (biopsy)
by immunofluorescence.
•The antibody antigen complex that results is formed and fixed in the tissues or
the cell surface.
•The result of antibodies binding to cell surface receptors is:
•Complement activation leading to cell lysis mast cell activation and neutrophil
recruitment
•The antibody antigen complex recruits cells directly through Fc interactions.
•The arrival of cells with cytotoxic capabilities i.e. neutrophils, monocytes,
eosinophils and killer cells, may lead to a mechanism of damage described as
antibody-dependent cell-mediated cytotoxicity (ADCC).

30. •Antibody binding can also result in altered expression of cell surface receptors,
resulting in the reduced ability of the target cell to function normally.
•The diseases that arise as a result of tissue damage in type II hypersensitivity
are varied, and the clinical picture depends on target tissue and antibody mode
of action.
•An example of a Type II reaction is an acute transfusion reaction, which is
when an inappropriate blood transfusion is administered and a patient is given
blood not matching their ABO type.
•This leads to activation of complement and widespread haemolysis by tumour
necrosis factor and other interleukins, which can be fatal.
•Type II is distinguished from Type III by the location of the antigens – in Type II,
the antigens are cell bound, whereas in Type III the antigens are soluble.

32. •Type III Hypersensitivity
•Type III hypersensitivity is also known as immune complex hypersensitivity.
•The reaction may be general (e.g., serum sickness), or may involve individual
organs including skin, kidneys, lungs, blood vessels or other organs.
•This reaction may be the pathogenic mechanism of diseases caused by many
microorganisms.
•The reaction may take 3 - 10 hours after exposure to the antigen
•It is mediated by soluble immune complexes, mostly of the IgG class, although
IgM may also be involved.
•The antigen may be exogenous (chronic bacterial, viral or parasitic infections),
or endogenous (non-organ specific autoimmunity: e.g., systemic lupus
erythematosus (SLE)).

33. •The antigen is soluble and not attached to the organ involved but the antibody-
antigen complexes can be deposited at tissues or form inside them, resulting in
damage due to complement and cellular recruitment and activation.
•Primary components are soluble immune complexes and complement (C3a, 4a
and 5a).
•The damage is caused by platelets and neutrophils.
•The lesion contains primarily neutrophils, and deposits of immune complexes
and complement.
•Macrophages infiltrating in later stages may be involved in the healing process.
•The affinity of antibody and size of immune complexes are important in
production of disease, and determining the tissue involved.
•Diagnosis involves examination of tissue biopsies for deposits of
immunoglobulin and complement by immunofluorescence microscopy.

34. •The presence of immune
complexes in serum, and
complement depletion are
also diagnostic.
•Treatment includes anti-
inflammatory agents.

35. •Type IV Hypersensitivity
•Type IV hypersensitivity is also known as cell mediated or delayed type
hypersensitivity (DTH).
•This reaction mainly occurs in response to mycobacteria and other similar
organisms which the immune system has difficulty eliminating.
•The classical example of this hypersensitivity is tuberculin (Mantoux) reaction
which peaks 48 hours after the injection of antigen (purified protein derivative
(PPD) or old tuberculin).
•The defining features of this reaction is the infiltration of cells appearing 24
hours after challenge.
•The main cell types found in the lesion are combinations of macrophages and
lymphocytes.
•If the antigen persists, the inflammation becomes chronic, and the
macrophages in the lesion fuse, forming giant cells and epithelioid cells.
•The reaction can range from localised redness and swelling to caseating
(yellowing/“turning to cheese”) necrosis.

36. •Type IV hypersensitivity is involved in the pathogenesis of many autoimmune
and infectious diseases e.g. tuberculosis, leprosy, blastomycosis,
histoplasmosis, toxoplasmosis, leishmaniasis, etc., and granulomas (which form
when the immune system attempts to wall off substances that it perceives as
foreign but is unable to eliminate; A granuloma is therefore a special type of
inflammation that can occur in a wide variety of diseases).
•Within a granuloma, there is extensive tissue damage with fibrosis and
calcification.
•Serious clinical consequences can arise if the reaction takes place in the lungs,
liver or bone.
•Another form of delayed hypersensitivity is contact dermatitis (poison ivy,
chemicals, heavy metals, etc.) in which the lesions are more papular (i.e.
characterised by the appearance of papules which are small, solid, usually
inflammatory elevations of the skin that do not contain pus.)
•Type IV hypersensitivity can be classified into three categories depending on
the time of onset and clinical and histological presentation; Contact dermatitis,
tuberculin-type hypersensitivity, and granulomatous-type hypersensitivity

37. •Contact dermatitis occurs when haptens penetrate the skin with proximity to
epidermal and dermal cells, resulting in an inflammatory reaction.
•Dermal dendritic cells and Langerhans cells play an important role in antigen
presentation and sensitization of these haptens to CD4 and CD8 T-cell
lymphocytes.
•CD8 T cells secrete cytokines and other enzymes to recruit other immune cells
to the site of hapten exposure.
•Additionally, keratinocytes help in recruiting immune cells by secreting other
groups of cytokines such as IL-8, resulting in inflammation of the skin with
swelling, itchiness, and pain.
•Tuberculin-type hypersensitivity can be seen after intradermal injection of
purified protein derivative (PPD) called tuberculin (product of tuberculosis
bacillus), which produces measurable local induration and swelling, typically
measured in millimetres between 48 to 72 hours after the injection.

38. •The tuberculin test is a validated method to diagnose tuberculosis infection,
even if latent.
•Granulomatous-type hypersensitivity can occur in response to a variety of
antigens.
•Macrophages that engulfed antigens are unable to destroy them and recruit
several more macrophages to the site of these antigens.
•A collection of macrophages filled with intracellular antigens is termed
granuloma.
•One example of granulomatous-type hypersensitivity is sarcoidosis disease,
which is a systemic granulomatous disease of unknown cause, with a wide
variety of clinical presentations.
•Sometimes, sarcoidosis is called reduced type four hypersensitivity due to the
slow progression of this disease.

39. Delayed hypersensitivity (DTH) reactions
TYPE REACTION TIME
CLINICAL
APPEARANCE
HISTOLOGY ANTIGEN AND SITE
Contact 48-72 hr Eczema
Lymphocytes, followed
by macrophages;
oedema of epidermis
Epidermal ( organic
chemicals, poison ivy,
heavy metals, etc.)
Tuberculin 48-72 hr Local induration
Lymphocytes,
monocytes,
macrophages
Intradermal
(tuberculin, lepromin,
etc.)
Granuloma 21-28 days Hardening
Macrophages,
epithelioid and giant
cells, fibrosis
Persistent antigen or
foreign body presence
(tuberculosis, leprosy,
etc.)

40. •The mechanisms of damage in delayed hypersensitivity include T lymphocytes
and monocytes and/or macrophages.
•Cytotoxic T cells (CD8) cause direct damage, whereas helper T (TH1) cells
secrete cytokines which activate CD8 cells, and recruit and activate monocytes
and macrophages, which cause the bulk of the damage.
•Corticosteroids and other immunosuppressive agents are used in treatment.

41. Comparison of Different Types of hypersensitivity
Type-I
(anaphylactic)
Type-II
(cytotoxic)
Type-III
(immune complex)
Type-IV
(delayed type)
Characteristics
Antibody IgE IgG, IgM IgG, IgM None
Antigen Exogenous Cell surface Soluble Tissues & organs
Response time 15-30 minutes Minutes-hours 3-8 hours 48-72 hours
Appearance Weal & flare Lysis and necrosis
Erythema and oedema,
necrosis
Erythema and induration
Histology
Basophils and
eosinophil
Antibody and
complement
Complement and
neutrophils
Monocytes and
lymphocytes
Transferred with Antibody Antibody Antibody T-cells
Examples
Allergic asthma, hay
fever
Erythroblastosis
Fetalis, Goodpasture's
nephritis
SLE, farmer's lung
disease
Tuberculin test, poison
ivy, granuloma

42. •Additional reading
•http://pubs.sciepub.com/ijcd/3/4/8/ - increasing prevalence of autoimmunity
•https://www.ncbi.nlm.nih.gov/books/NBK562228/#:~:text=Type%20four%20hypersensit
ivity%20reaction%20is,avoided%20to%20treat%20this%20condition.
•https://teachmephysiology.com/immune-system/immune-responses/hypersensitivity-
reactions/
•https://www.brainkart.com/article/Type-II-%28Cytotoxic%29-Hypersensitivity_17975/
•https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4518692/
•https://www.theguardian.com/science/2022/jan/08/global-spread-of-autoimmune-
disease-blamed-on-western-diet
•https://www.britannica.com/science/autoimmunity
•https://pathology.jhu.edu/autoimmune/definitions
•https://www.immunology.org/public-information/bitesized-
immunology/cells/regulatory-t-cells-tregs