BASIC IMMUNOLOGY

1. BASIC IMMUNOLOGY SAMUEL AGUAZIM(MD)

2. IMMUNOLOGY • Today's lecture is going to summarize the whole course and there are going to be things that you may not understand. Also, they are going to be some points that are very summarized, because later on you will have a whole lecture on it. • The goal of this lecture is to give an outline of the course immunology

3. DEFINITION • Immunology is the study of our protection from foreign macromolecules or invading organisms and our responses to them. • Host – e.g. me!!!! • Foreign macromolecule, antigen – e.g. virus protein, worm, parasite (Everything that should not be in my body)

4. DEFINITION • Immunity: this word comes from the Latin word immunituswhich means "freedom from "And in this case it means freedom from disease, and freedom from infection. • So, although our world is full of microbes we do not fall ill because of the blessing of our immune system

5. DEFINITION • Immune system- collection of organs, tissues, cells and soluble factors that allow humans to post defenses against viruses, bacteria and tumor cells.

6. Primary Lymphoid Organs • Bone Marrow • Thymus • Spleen and liver in the fetal period

7. Secondary Lymphoid organs • Lymph Nodes • Spleen • Tonsils • Mucosa-associated lymphoid tissue (MALT) • gut-associated lymphoid tissue (GALT) • bronchus-associated lymphoid tissue (BALT

8. BONE MARROW • -PRIMARY LYMPHOID ORGAN • -site of hematopoiesis • -site of B cell maturation • - found in the axial skeleton, cranium, ribs, long bones • - produce the PLURIPOTENT STEM CELL • -stimuli for differentiation: Colony-stimulating factor, erythropoietin, thymosin, antigens, IL-3, IL-6

9. THYMUS • site of T cell maturation (final maturation will occur however in the secondary lymphoid organs) • embryology: derived from the 3rd and 4th pharyngeal pouches; maximum weight is at puberty then involutes during adulthood • consists of two zones: cortex, which has immature T cells, epithelial cells and macrophages; and the medulla, which mature T cells and Hassal corpuscles ( concentric follicles composed of dead and dying reticular cells, macrophages and neutrophils)

10. LYMPH NODES • secondary organs in the immune system; most common site for the production of the adaptive immune response since they filter the lymph and are exposed to the antigens • B cells are found in the cortex, while the T cells are found in the paracortex • Germinal centers may be develop in the cortex during an immune response depending on antigen stimulation; composed mainly of T cells, B cells, and macrophages; the B cells develop into PLASMA CELLS in the germinal centers

11. LYMPH • plasma which is filtered out into the body tissues will not completely be reabsorbed into the venules; the “ excess” plasma is called interstitial fluid and will enter the lymphatic vessels as LYMPH

12. SPLEEN • classified as a peripheral lymphoid organ • it is a primary lymphoid organ only during the fetal period • function: filters blood, protects the body against blood-borne pathogens, clears old and defective RBC • consist of two important zones: • 1. White pulp • periarteriolar lymphatic sheath (PALS) : has T cells • Marginal zones: has B cells • Primary follicles: has B cells and dendritic cells • 2. Red pulp • site of blood filtration • has sinusoids, which are filled with RBC

13. GALT • GUT-ASSOCIATED LYMPHOID TISSUES (GALT) • present in the submucosa and lamina propria of the GIT • FUNCTION: site of the immune response to ingested antigens and microbes; endocytose microbes and antigens are presented to the T cells; B cells are activated and form germinal centers; where they differentiate in to plasma cells; plasma cells secrete IgA • Includes the : Peyers patches in the small intestine • Lamina propria beneath the mucosa • Lymphocytes in the mucosa

14. BALT • BRONCHUS-ASSOCIATED LYMPHOUD TISSUE (BALT) • includes the : tonsils • lymphoid tissues under the respiratory mucosa • types of tonsils: • 1. palatine tonsils in the oropharynx • 2. lingual tonsils at the base of the tongue • 3. pharyngeal tonsils in the posterior wall of the nasopharynx (during hypertrophy, they are called adenoids) • Lymph node swelling is due to lymphocyte trapping and division

15. CELLS OF THE IMMUNE SYSTEM • Monocytes-macrophages • Dendritic cells • Granulocytes(polymorphonuclear leukocytes) • neutrophils • Eosinophils • basophils • Lymphocytes • B lymphocytes • T lymphocytes • Natural Killer cells

16. Functions of M and M • Phagocytosis • secrete mediators of inflammation • Opsonization (C3b) • Antigen-presenting cells (MHC)

17. MONOCYTE-MACROPHAGES • Stimuli: LYMPHOKINES INTERFERON – gamma • causes increased lysosomal enzyme production • increased chemotactic abilities

18. Monocytes-macrophages • liver macrophages – Kupffer cells • Brain macrophages – Microglial cells • Lung macrophages – alveolar macrophages • Macrophages in granulomas – epitheloid cells • Cluster of epitheloid cells – giant cells

19. DENDRITIC CELLS • - also antigen-presenting cells; found in the peripheral blood and lymphoid organs • - example: Langerhans cell in the skin • Reticulum cellsin the spleen and lymph nodes

20. GRANULOCYTES • NEUTROPHILS • first cell in acute inflammation • containazurophilic granules with myeloperoxidase; also has lactoferrin • generate hydrogen peroxide and toxic oxygen radicals • contain receptors for IgG and C3b( for opsonization)

21. EOSINOPHILS • EOSINOPHILS • cells involved in late inflammatory reactions, especially allergies and parasitic infections • chemotactic factors include: histamine, C5a, LTB4, PAF, ECF-A • contains Major Basic Proteins (harmful to worms), Peroxidase ( harmful to microbes) • contain receptors for complement

22. BASOPHILS • BASOPHILS • - have receptors for IgE • - binding with IgE causes release of histamine

23. T LYMPHOCYTES • divided into two major types depending on their CD proteins • Th1 cell: promote cytotoxic T-cell (CD8+ cells) responses and delayed hypersensitivity reactions; recognize APC with MHC class I • Th2 cell: stimulate B cells to proliferate and differentiate into antibody producing cells • Both Th1 and Th2 have CD4+ proteins; recognize APC with MHC class II

24. NATURAL KILLER CELLS • kill tumor cells and viruses without the need for MHC • mediate ADCC (antibody-mediated cellular cytotoxicity) • activated by interferon – gamma and IL-2

25. THE IMMUNE RESPONSE • Innate immunity • Acquired Immunity • Humoral immune response • Cellular immune response

26. INNATE IMMUNITY • -natural immunity present at birth • -the response does not increase upon repeated antigen exposure • -first line of defense against antigens since it allows elimination without previous exposure • --skin, mucous membranes, tears, saliva, sweat

27. ACQUIRED IMMUNITY • -occurs late in fetal life, continues to develop into childhood • -antibodies on B cells and T-cell receptors recognize specific antigens • -anamnestic response causes production of memory T cells and B cells

28. ANTIGEN • any substance which is bounded by an antibody or T cell receptor • Immunogen: a substance that induces a specific immune response

29. Hapten • Hapten: • a substance that is non-immunogenic ; small molecules which could never induce an immune response when administered by themselves but which can when coupled to a carrier molecule( example; penicillin)

30. Immunogen: a substance that induces a specific immune response

31. - Factors which contribute to immunogenicity • the immune system normally recognize foreign substances • the larger the molecule, the more antigenic it is • the more complex the structure, especially proteins with secondary, tertiary or quarternary structures are immunogenic • lipids are usually not immunogenic, however, when they are coupled to proteins, they trigger delayed hypersensitivity responses (they do not stimulate the production of antibodies) • polysaccharides are also good immunogens • nucleic acids are poor immunogens

32. MAJOR HISTOCOMPATIBILITY COMPLEX (MHC) • -set of GENES which encode for proteins that regulate the immune response • -class I and II: encode for cell surface proteins • -class III: encode for complement proteins • -HUMAN LEUKOCYTE ANTIGENS (HLA): MHC in humans, located on the short arm of chromosome 6

33. HLA CLASS I • -found on all the surfaces of nucleated cells and platelets • -bind endogenous peptide and present them to CD8+ cytotoxic T cells. • -has 3 types: HLA-A, HLA-B AND HLA-C • -recognize cells which have been infected by viruses, bacteria, parasites and tumors

34. HLA CLASS II • -found only on the cell surfaces of: dendritic cells, Langerhans cells, activated macrophages, B cells, thymic epithelial cells • -binds exogenous peptides and the formed complex is necessary for antigen recognition by T helper cells (CD4+ cells) • -has 3 types: HLA-DP, HLA-DQ, HLA-DR • -recognizes cell which have been infected by bacteria, parasites or injected proteins • HLA CLASS III • -genes which encode for complement components like C2

35. ANTIBODY • produced by B cells • variable regions: amino terminal • constant regions: carboxy terminal

36. Functional parts of the Immunoglobulin • Fab fragment : portion which bind the antigen • Fc fragment – portion which binds complement

37. There are five classes of Immunoglobulins - The basic form of antibodies • -based on the structural differences in the constant regions of the heavy chains: • a. IgG – gamma heavy chains • b. IgA – alpha heavy chains • c. IgM – mu heavy chains • d. IgE – epsilon chains • e. IgD – delta chains

38. Class switching • constant part of heavy chain: changed • variable region of the heavy chain: unchanged • class switching does not affect antigen specificity • antibody retains affinity for the same antigens, but can interact with different effector molecules.

39. IgG • most versatile • Most abundant • only class of Ig that crosses the placenta. • fixes complement • binding to cells like macrophages, monocytes, PMN's and some lymphocytes: Fc receptors

40. IgA • 2nd most common serum Ig • major class of Ig in secretions • local (mucosal) immunity • Occurs in bodily secretions • Found in breast milk • Attaches to the lining of the digestive, respiratory, and gastrointestinal tract • Transported through epithelial cells • Attaches to microbes before they invade tissues • Activates complement • Exists as a dimer

41. IgM • third most common • first Ig to be made by the fetus • first Ig to be made by a virgin B cells • good complement fixing Ig; • good agglutinating Ig; • binds to some cells via Fc receptors

42. IgD • primarily found on B cell surfaces • functions as a receptor for antigen • It may help in immune responses • It also may be active in allergic responses

43. IgE • least common serum Ig • allergic reactions • parasitic helminth diseases • IgE is found primarily in tissues and bodily fluids

44. TYPES OF ACQUIRED IMMUNE RESPONSEA. HUMORAL • 1. PRIMARY IMMUNE RESPONSE • -first response to antigenic stimuli • -no antibodies can be measured in the 1st 3 to 5 days since the Th and B cells are still being activated • -once antibodies are produced, IgM is the type first detected; later on, class switching occurs, and IgG predominates • -IgA may also be detected depending on the presence of an oral or mucosal antigen • 2. SECONDARY IMMUNE RESPONSE • -also known as a memory or anamnestic response to previously encountered antigen • -mediated by the memory B and T cells • -IgA may also be detected based on the type of antigen; IgE may be seen in response to helminths

45. B. CELLULAR IMMUNE RESPONSE • -major cell type needed is the T cell • 1. APC present the antigens to T helper cells through the help of MHC class II; CD4+ cells activate NK cells or macrophages and neutrophils • 2. T helper cells also binds to B cells and secrete cytokines , IL-2 and IFN – gamma: proliferation and differentiation of cytotoxic T cells and macrophages • 4. cytotoxic T cells (CTL) will bind to cells infected by viruses or tumors (through the help of MHC Class I); enzymes are secreted which kill the cells

46. REGULATION OF THE IMMUNE RESPONSE • Immunosuppression: • -active immunologic unresponsiveness • -Interferon – gamma and interleukins can suppress T helper response , leading to less activation of the B cells • -X-ray and UV radiation: eliminates lymphocytes, predominately the B cells • -surgical removal of thymus, Lymph nodes and spleen

47. CORTICOSTEROIDS • -Corticosteroids can cause: • *peripheral blood lymphopenia • *inhibit RNA and DNA synthesis • *decrease macrophage responses • *decrease monocytechemotaxis • *decrease IgG response

48. -other immunosuppressive drugs: • *purine or pyrimidine analogs • *folic acid antagonists • *alkylating agents

49. COMPLEMENT SYSTEM • proteins found in the blood and tissue fluids • important in opsonization • regulation of inflammatory response • killing cells and microbes