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1. INNATE IMMUNITTY COMPONENTS OF INNATE IMMUNITY

2. Classification Innate immunity may be classified as (a) individual immunity (b) racial immunity (c) species immunity.

3. Individual immunity Individual immunit y denotes resistance t o infection , whic h varies withi n different individuals in the same race and species and is genetically determined. Fo r example , i f one homozygous twi n develops tuberculosis , ther e i s a very high possibility that the other twin will also develop tuberculosis. But in heterozygous twins, there is a very low possibility of the other twin suffering from tuberculosis.

4. Racial immunity Racial immunity denotes a difference in susceptibility or resistance to infection among different races within a same species. For example, races with sickle cell anemia prevalent in Mediterranean coast are immune to infection caused by malaria parasite Plasmodium falciparum . This is due to a genetic abnormality of erythrocytes, resulting in sickleshaped erythrocytes that prevent parasitization by P. falciparum . Similarly, individuals with a hereditary deficiency of glucose6-phosphatase dehydrogenase are also less susceptible to infection by P. falciparum

5. 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. The exact reason for such type of immunity is not known.

6. Phagocytosis Cells: Macrophages, neutrophils , and dendritic cells in tissues and monocytes in the blood are the main cell types that carry out phagocytosis

7. General Process The rough various cell surface receptors they recognize microbes such as bacteria, extend their plasma membrane to engulf them, and internalize them in phagosomes (endosomes resulting from phagocytosis Lysosomes then fuse with the phagosomes, delivering agents that kill and degrade the microbes. Neutrophils are a second major type of phagocyte, usually recruited to sites of infection. Finally, dendritic cells also can bind and phagocytose microbes. uptake and degradation of microbes by dendritic cells play key roles in the initiation of adaptive immune responses. In addition to triggering phagocytosis,.

8. Microbes are Recognized by Receptors on Phagocytic Cells some receptors directly recognize specific conserved molecular components on the surfaces of microbes, such as cell wall components of bacteria and fungi. These conserved motifs, usually present in many copies on the surface of a bacterium, fungal cell, parasite, or virus particle, are called pathogen-associated molecular patterns (PAMPs). can be expressed by microbes whether or not the microbes are pathogenic Or Microbe-associated molecular patterns (MAMPs).

9. Pattern Recognition Receptors PRR The receptors that recognize PAMPs are called pattern recognition receptors (PRRs). Some PRRs that, after PAMP binding, do not activate phagocytosis but trigger other types of responses. Most PAMPs that induce phagocytosis are cell wall components, including complex carbohydrates such as mannans Glucans lipopolysaccharides (LPS) other lipid-containing molecules peptidoglycans

10. Opsonization (Indirect activation) activation of phagocytosis can also occur indirectly, by phagocyte recognition of soluble proteins that have bound to microbial surfaces, thus enhancing phagocytosis, a process called opsonization (from the Greek word for “to make tasty”). Many of these soluble phagocytosis-enhancing proteins (called opsonins) also bind to conserved, repeating components on the surfaces of microbes such as carbohydrate structures, lipopolysaccharides, and viral proteins; hence they are sometimes referred to as soluble pattern-recognition proteins. Once bound to microbe surfaces, opsonins are recognized by membrane opsonin receptors on phagocytes, activating phagocytosis

11. Role of Opsonins the two surfactant collectin proteins, SP-A and SP-D, are found in the blood as well as in mucosal secretions in the lungs and elsewhere, where they function as opsonins. After binding to microbes they are recognized by the CD91 opsonin receptor and promote phagocytosis by alveolar and other macrophage populations. function of SP-A and SP-D contributes to clearance of the fungal respiratory pathogen Pneumocystis carinii , a major cause of pneumonia in individuals with AIDS. Mannose-binding lectin (MBL), a third collectin with opsonizing activity, is found in the blood and respiratory fluids.

12. Oxidative Attack Oxidative attack on the phagocytosed microbes, which occurs in neutrophils, macrophages, and dendritic cells , employs highly toxic reactive oxygen species (ROS) reactive nitrogen species (RNS)

13. ROS and RNS The reactive oxygen species are generated by the phagocytes’ unique NADPH oxidase enzyme complex (also called phagosome oxidase) which is activated when microbes bind to the phagocytic receptors. THE RESPIRATORY BURST The oxygen consumed by phagocytes to support ROS production by NADPH oxidase is provided by a metabolic process known as the respiratory burst, during which oxygen uptake by the cell increases severalfold. NADPH oxidase converts oxygen to superoxide ion (• O 2 ); other ROS generated by the action of additional enzymes are hydrogen peroxide (H 2 O 2 ), and hypochlorous acid (HClO), the active component of household bleach

14. RNS The generation of RNS requires the transcriptional activation of the gene for the enzyme inducible nitric oxide synthase (iNOS, or NOS2)—called that to distinguish it from related NO synthases in other tissues. Expression of iNOS is activated by microbial components binding to various PRRs. iNOS oxidizes L-arginine to yield L-citrulline and nitric oxide (NO), a potent antimicrobial agent. In combination with superoxide ion (• O2 ) generated by NADPH oxidase, NO produces an additional reactive nitrogen species, peroxynitrite (ONOO) and toxic S- nitrosothiols .

15. Cont …….. Collectively the ROS and RNS are highly toxic to phagocytosed microbes due to the alteration of microbial molecules through oxidation, hydroxylation, chlorination, nitration, and S- nitrosylation , along with formation of sulfonic acids and destruction of iron-sulfur clusters in proteins. One example of how these oxidative species may be toxic to pathogens is the oxidation by ROS of cysteine sulfh ydryls that are present in the active sites of many enzymes, inactivating the enzymes. ROS and RNS also can be released from activated neutrophils and macrophages and kill extracellular pathogens.

16. CELLS OF INNATE IMMUNITY NEUTROPHILS MACROPHAGES NATURAL KILLER CELLS DENTRITIC CELLS

17. Neutrophils Activity Range: Bacteria and fungi Mode of Action Phagocytosis TLR Opsonization ROS+RNS Antibacterial compounds(protease,lysozyme,defensins,cathelicidins)

18. Macrophages Activity range: Bacteria, fungi, protozoa, parasites Mode of action: TLR Cytokines receptors APCs-MHC-II Proteins iNOS Interlukins and tissue necrosis factors (IL1,IL6 & TNF α)

19. NK CELLS ACTIVITY Viruses Mode of action: Lysis Cytokines Unlike B and T lymphocytes, whose receptors have tremendous diversity for foreign antigens, NK cells express a limited set of invariant, nonrearranging receptors that enable the cells to be activated by indicators of infection, cancer, or damage that are expressed by other cells. Again unlike B and T cells, which require days of activation, proliferation, and differentiation to generate their protective antibody and cell-mediated

20. Dendritic cells Link b/w innate and adaptive TH and TC cells interaction APCs TLR

21. Types of acquired immunity Types of acquired immunity Acquired immunity against a microbe may be induced by the host’s response to the microbe or by transfer of antibodies or lymphocytes specific for the microbes. It is of two types: Active Immunity Passive Immunity.

22. Active immunity The immunity induced by exposure to a foreign antigen is called active immunity. Active immunity is the resistance developed by an individual after contact with foreign antigens, e.g., microorganisms. This contact may be in the form of: ■ clinical or subclinical infection ■ immunization with live or killed infectious agents or their antigens, ■ exposure to microbial products, such as toxins and toxoids.

23. MECHANISM In all these circumstances, the immune system of the host is stimulated to elicit an immune response consisting of antibodies and activated helper T (TH) cells and cytotoxic T lymphocytes/cells (CTLs). Active immunity develops after a latent period, during which immunity of the host is geared up to act against the microorganism. Hence it is slow in onset, especially during this primary response. However, once the active immunity develops, it is long-lasting and this is the major advantage of the active immunity.

24. TYPES OF ACTIVE IMMUNITY The active immunity is of two types Natural Active Immunity Artificial Active Immunity.

25. CONT.. Natural active immunity : It is acquired by natural clinical or subclinical infections. Such natural immunity is long lasting. Fo r example , individual s sufferin g from smallpo x become immun e t o second attack of the disease. Artificial active immunity: It is induced in individuals by vaccines. There is a wide range of vaccines available against many microbial pathogens. Thes e ma y be liv e vaccines, killed vaccines, or vaccines containin g bacterial products

26. Mediators of active immunity: Active immunity is mediated by humoral immunity and cell-mediated immunity. These two types of immunities are mediated by different components of the immune system and function in different ways to kill different types of pathogens

27. Mediators of active immunity Humoral immunity : It is mediated by molecules in the blood and mucosal secretions called antibodies. The antibodies are secreted by a subset of lymphocytes known as B cells. The antibodies recognize microbial antigens, combine specifically with the antigens, neutralize the infectivity of microbes, and target microbes for elimination by various effector mechanisms. Humoral immunity is the principal defense mechanism against extracellular microbes. Cell-mediated immunity It is mediated by both activated TH cells and CTLs. Cytokines secreted by TH cells activate various phagocytic cells, enabling them to phagocytose and kill microorganisms. This type of cell-mediated immune response is especially important against a host of bacterial and protozoal pathogens. CTLs play an important role in killing virus-infected cells and tumor cells. They act by killing altered self-cells.

28. PASSIVE IMMUNITY When immunity is conferred by transfer of serum or lymphocytes from a specifically immunized individual, it is known as passive immunity. This is a useful method for conferring resistance rapidly , i.e., without waiting for the development of an active immune response.

29. Passive immunity TYPES Natural passive immunity: It is observed when IgG is passed from mother to fetus during pregnancy. This forms the basis of prevention of neonatal tetanus in neonates by active immunization of pregnant mothers. It is achieved by administering tetanus toxoid to pregnant mothers during the last trimester of pregnancy. This induces production of high level of antibodies in mother against tetanus toxin, which are subsequently transmitted from mother to fetus through placenta. The antibodies subsequently protect neonates after birth against the risk of tetanus. Natural passive immunity is also observed by passage of IgA from mother to newborn during breast feeding.

30. Artificial passive immunity 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 antisera makes large amounts of antibodies available in the recipient host to neutralize the action of toxins. The preformed antibodies against rabies and hepatitis A and B viruses, etc. given during incubation period prevent replication of virus, and hence alter the course of infection. Immediate availability of large amount of antibodies is the main advantage of passive immunity. However, short lifespan of these antibodies and the possibility of hypersensitivity reaction, if antibodies prepared in other animal species are given to individuals who are hypersensitive to these animal globulins (e.g., serum sickness), are the two noted disadvantages of passive immunity

31. Herd Immunity Herd immunity refers to an overall level of immunity in a community. Eradication of an infectious disease depends on the development of a high level of herd immunity against the pathogen. Epidemic of a disease is likely to occur when herd immunity against that disease is very low indicating the presence of a larger number of susceptible people in the community.

32. ADAPTIVE IMMUNITY ANTIGENIC SPECIFICITY DIVERSITY MEMEORY SELF /NON SELF RECOGNITION

33. Specificity and diversity Recognizes portions of a single complex protein, polysaccharide, or other macromolecule The parts of such antigens that are specifically recognized by individual lymphocytes are called determinants or epitopes. This fine specificity exists because individual lymphocytes express membrane receptors that are able to distinguish subtle differences in structure between distinct epitopes. Clones of lymphocytes with different specificities are present in unimmunized individuals and are able to recognize and respond to foreign antigens.

34. Diversity The total number of antigenic specificities of the lymphocytes in an individual, called the lymphocyte repertoire , is extremely large. It is estimated that the immune system of an individual can discriminate 10 7 to 10 9 distinct antigenic determinants. This ability of the lymphocyte repertoire to recognize a very large number of antigens is the result of variability in the structures of the antigen-binding sites of lymphocyte receptors for antigens, called diversity. In other words, there are many different clones of lymphocytes that differ in the structures of their antigen receptors and therefore in their specificity for antigens, contributing to a total repertoire that is extremely diverse

35. Memory. Exposure of the immune system to a foreign antigen enhances its ability to respond again to that antigen. Responses to second and subsequent exposures to the same antigen, called secondary immune responses, are usually more rapid, larger, and often qualitatively different from the first, or primary, immune response to that antigen . Immunologic memory occurs because each exposure to an antigen generates long-lived memory cells specific for the antigen, which are more numerous than the naive T cells specific for the antigen that exist before antigen exposure. In addition, these memory cells have special characteristics that make them more efficient at responding to and eliminating the antigen than are naive lymphocytes that have not previously been exposed to the antigen. For instance, memory B lymphocytes produce antibodies that bind antigens with higher affinities than do antibodies produced in primary immune responses, and memory T cells react much more rapidly and vigorously to antigen challenge than do naive T cells.

36. Clonal expansion . Lymphocytes specific for an antigen undergo considerable proliferation after exposure to that antigen. The term clonal expansion refers to an increase in the number of cells that express identical receptors for the antigen and thus belong to a clone. This increase in antigen-specific cells enables the adaptive immune response to keep pace with rapidly dividing infectious pathogens.

37. Specialization. the immune system responds in distinct and special ways to different microbes, maximizing the effectiveness of antimicrobial defense mechanisms. Thus, humoral immunity and cell-mediated immunity are elicited by different classes of microbes or by the same microbe at different stages of infection (extracellular and intracellular), and each type of immune response protects the host against that class of microbe. Even within humoral or cell-mediated immune responses, the nature of the antibodies or T lymphocytes that are generated may vary from one class of microbe to another.

38. Contraction and homeostasis .All normal immune responses wane with time after antigen stimulation, thus returning the immune system to its resting basal state, a state that is called homeostasis This contraction of immune responses occurs largely because responses that are triggered by antigens function to eliminate the antigens, thus eliminating an essential stimulus for lymphocyte survival and activation. Lymphocytes, other than memory cells, that are deprived of these stimuli die by apoptosis.

39. Nonreactivity to self. One of the most remarkable properties of every normal individual’s immune system is its ability to recognize, respond to, and eliminate many foreign (non-self) antigens while not reacting harmfully to that individual’s own (self) antigenic substances. Immunologic unresponsiveness is also called tolerance. Tolerance to self antigens, or self-tolerance, is maintained by several mechanisms. These include eliminating lymphocytes that express receptors specific for some self antigens, inactivating self-reactive lymphocytes, or suppressing these cells by the actions of other (regulatory) cells. Abnormalities in the induction or maintenance of self-tolerance lead to immune responses against self (autologous) antigens, which may result in disorders called autoimmune diseases.

40. LYMPHOCYTES AND APCS Produced in bone marrow B and T lymphocytes