1. Diseases of Immunity (Immunopathology)

2. Introduction
The physiological function of the immune system is to protect indivisual from infectious pathogens. There are two mechanisms for this protection:
Innate (natural or native) immunity
Adaptive immunity

3. Innate Immunity: Are defense mechanisms that are present even before infection and protect indivisual against infection, they include 1-epithelial barriors 2-phagocytic cells (neutrophils, macrophages) 3-natural killer cells 4-plasma protiens including protiens of the compliment system.

4. Adaptive immunity:
Which includes two major types
Cell mediated immunity responsible for defense against intracellular microbes e.g. mycobacterium, viruses, tumor cells parasites. It is mediated by T lymphocytes.
Humoral immunity protects against extracellular bacteria and their toxins. It is mediated by B lymphocytes and their secreted antibodies ( immunoglobulin).

5. All these mechanisms of adaptive immunity may cause diseases e. g
All these mechanisms of adaptive immunity may cause diseases e.g. immune deficiency state leads to increase susceptibility to infection while a hyperactive immune system may cause fatal disease e.g. overwhelming allergic reaction.

6. Cell mediated Immunity
T lymphocytes
Are derived from the thymus, they constitute 60% to 70% of lymphocytes in peripheral blood. Also present in the paracortical area of lymph nodes and in the periarteriolar sheath of the spleen. Each lymphocyte expresses certain receptor on their surface called antigen- specific T-cell receptor (TCR) which recognizes peptide antigen that are displayed by major histocompatibility complex (MHC) molecules ( on the surface of antigen presenting cells) so T cells requires MHC molecules on the surface of antigen presenting cell for its activation.

9. Depending on the presence of a specific membrane glycoprotein receptors on T cell surface, T cells are subdivided into:
CD4+ T cells ( T helper cells) constitute 60% of T cells, they express CD4+ T cells on cell surface. This CD4 molecule binds to class II MHC molecule on the surface of antigen presenting cell.
CD8+ T cells ( Cytotoxic T cells) : constitute 30% of T cells, they express CD8 molecule on their surface and bind to class I MHC molecule.

10. When an antigen binds to TCR on surface of T cell and CD4 and CD8 molecules bind to specific MHC molecules, T cells become activated and release locally acting proteins called cytokines. These cytokines activate more T cells resulting in elimination of antigen. At the same time, some of activated T cells differentiate into memory cells which provide immunity and respond rapidly after subsequent exposure to the same antigen.
Cytokines secreted by CD4+ T cells also stimulate other cells of the immune system e.g. B cells, macrophages and NK cells.

11. T cell activation

14. CD4+ T cells are also subdivided into two types depending on cytokine they produce:
T helper 1(TH 1) secrete interleukin 2 (IL-2) and interferon-ɣ(IFN-ɣ).
T helper 2 (TH 2) cells secrete IL-4, IL-5 and IL-13.

15. B- Lymphocytes:
Are derived from bone marrow and constitute 10% to 20% of circulating peripheral lymphocytes and present in the lymph nodes, white pulp of spleen, tonsils and extralymphatic organs like GIT. In the lymph node, they aggregate in lymphoid follicles and once they are activated, they develop a pale-staining germinal centers.
The surface of B cell contains IgM which acts as a receptor for antigen binding. Other receptors on the surface include: complement receptors and Fc recepts for binding of Fc portion of immunoglobulin.

18. The activation of B cells requires the help of CD4+ T helper cells which first recognize the antigen ( presented by antigen presenting cells in association with specific MHC molecule). Once T cells are activated they start to secrete cytokines and tumor necrosis factor (TNF) which activate B cells that differentiate into plasma cells, these are antibody secreting cells, they secrete immunoglobulin which mediate humoral immunity

20. Fab region
Fc portion

21. These immunoglobulin are of five types
IgG is the most abundant type present in the plasma, tissue fluids and can cross the placenta
IgA is the next most common type present in plasma and in saliva and intestinal secretion and has a protective mechanism in the mucosa of GIT.

22. IgM is the largest Ig found only in plasma and the first immunoglobulin which appear after antigenic stimulation of B cells
IgE present in serum and on the surface of mast cells and basophils. It is involved in protection against parasites and mediate allergic reaction.
IgD present in serum and surface of B cells

23. Macrophages Are part of mononuclear phagocytic system derived from blood monocytes. They are activated by interferon ɣ secreted from TH 1 subset of CD4+ T cells Functions of macrophages 1-phagocytosis of microbes and foreign antigens 2-enter delayed type hypersensitivity to provide protection against mycobacteria 3-enter in the humoral immunity by phagocytosis of microbes that are opsonized ( coated with IgG or C3b compliment component (opsonization)).

25. Natural killer cells Make up to 15% of peripheral blood lymphocytes but are larger than lymphocyte and do not contain receptors on their surfaces. They are part of innate immunity ( do not require previous sensitization for its activation). They help to kill tumor cells, virally infected cells, and IgG coated target cells (antibody dependent cell mediated cytotoxicity) by secreting cytokines such as IFNɣ and TNF.

27. Dendritic cells Are cells with cytoplasmic processes distributed in epithelial surfaces (interdigitating dendritic cells) and in the epidermis ( langerhan’s cells) and in the germinal center of lymphoid follicles of lymph nodes ( follicular dendritic cells). These cells are the most important antigen presenting cells for initiating primary immune response, they have many receptors on their surface that help to capture microbes from their site of entry at epithelial surfaces.

28. They migrate through afferent lymphatics to regional lymph nodes to present the antigen to CD4+ T cells which initiate immune response by secreting cytokines which activate B cells into plasma cells that produce immunoglobulins which neutralize and elemenate the antigen.

30. T cell activation

32. Major histocompatibility complex (MHC) or human leukocyte antigen (HLA) Are extremely important antigens for induction and regulation of immune reponse. The principle function of MHC is to bind to forgein antigen for presentation to T cells . (so CD8+ T cells recognize microbes only if presented as a complex with class I MHC molecules).

33. There are two classes of these antigens encoded by the corresponding genes Class I MHC antigen: is expressed on the surface of all nucleated cells and platelets. They bind to intracellular antigens such as viral antigen to form a complex on cell surface for presentation to CD8+ cytotoxic T cells

34. Class II MHC molecules is found on epithelial surfaces and present extracellular antigens e.g. extracellular microbes after formation of a complex on the cell surface that can be recognized by CD4+ T helper lymphocytes (so CD4+ T cells recognize microbes only if presented as a complex with class II MHC molecules).

35. Disorders of the Immune System
Hypersensitivity reactions
Autoimmune diseases (immune reaction against self)
Immunodeficiency syndromes ( genetically determined or acquired defects in some component of normal immune system).
Amyloidosis: a poorly understood disorder having immunologic association.

36. Hypersensitivity reactions Are immune responses that develop after contact with antigens. There are many types of these triggering antigens 1)Exogenous antigens: dusts, pollens, food, drugs, microbial agents, chemicals and blood. 2) Endogenous or tissue antigens: transfusion reaction, graft rejection, self (autologus) antigen.

37. On the basis of immunologic mechanism which mediates the disease, hypersensitivity reactions are classified into 4 types:
Type I (immediate) hypersensitivity.
Type II hypersensitivity ( antibody-mediated disorder)
Type III hypersensitivity ( immune complex mediated disorders)
Type IV hypersensitivity ( cell-mediated or delayed type).

38. Type I (immediate) hypersensitivity
A rapidly developing immunologic reaction occurring within minutes after the combination of an antigen to antibody bound to mast cells in individuals previously sensitized to that antigen. These reactions are called allergy and the antigen that elicit them is called allergen.

39. Local type I hypersensitivity has two phases The immediate ( initial) response: characterized by vasodilatation, vascular leakage, smooth muscle spasm, glandular, secretion. These changes become evident within 5 to 30 minutes after exposure to the antigen and subside in 60 minutes and may be followed by late-phase reaction.

40. Late-phase reaction: starts within the next 2 to 24 hours after allergen exposure and lasts for several days. Characterized by infiltration of tissue by eosinophils, neutrophils, basophiles, monocytes and lymphocytes with tissue destruction and damage of mucosal and epithelial surfaces.

41. Pathogenesis The main inflammatory cells which mediate type I reaction is mast cells and basophiles. Mast cells are derived from bone marrow and contain cytoplasmic granules filled with vasoactive amines. Type I reaction is mediated by IgE antibodies secreted from differentiated B cells. The surface of mast cells posses Fc receptor for the binding of Fc portion of IgE.

42. The sequence of events begins with the initial exposure to certain antigen or allergen (such as pollen, drugs, food) . These allergens stimulate induction of CD4+ lymphocytes of TH2 type. Once CD4+ lymphocytes recognize the antigen presented to it with antigen presenting cells, they start to secrete cytokines (IL4, IL5) which stimulate the production of IgE antibodies from B cells. IgE binds to Fc receptors on surface of mast cells and basophiles.

43. Re-exposure to the same antigen results in cross-linking of IgE on the surface of mast cells resulting in degranulation of mast cells and release of inflammatory mediators from granules in the cytoplasm of mast cells

48. There are two types of mast cell mediators: Primary mediators: are preformed mediators within mast cell granules: 1 – Histamine: is the most important of these mediators. It causes increased vascular permeability, vasodilatation, bronchoconstriction and increase mucus production. 2 – Adenosine induces bronchoconstriction. 3 – Heparin 4 – Proteases which activate complements

49. Secondary mediators 1 – Lipid mediators like archidonic acid produced from mast cell membrane phospholipids from which leukotrienes and prostaglandins are synthesized. Leukotrienes are very potent vasoactive substances produce severe vasodilatation, increased vascular permeability and bronchoconstriction ( more potent than histamine).

50. 2 - Cytokines: (TFN, IL1, IL4, IL5 and IL6) recruit and activate variety of inflammatory cells like neutrophils and eosinophils. These cells mediate tissue injury in late-phase reaction and produce epithelial cell damage. Eosinophils produce more leukotrienes which directly activate mast cell mediators resulting in amplification of inflammatory response (even in the absence of additional exposure to the allergen).

51. Because inflammation is a major component of late-phase reaction in type I hypersensitivity, its control usually requires anti-inflammatory drugs such as corticosteroid.

52. Clinical manifestations: Type I reaction is of two types Systemic reaction: follows injection of an antigen to which the host has become sensitized. Often within minutes, a state of shock is produced which is fatal (anaphylactic shock) e.g., pencillin or bee venom when administered as parenteral injection result in systemic anaphylaxis.

53. Within minutes of an exposure in sensitized host, itching, urticaria and skin erythema appears followed rapidly by profound respiratory difficulty (due to bronchoconstriction and increased mucus production) and laryngeal edema, systemic vasodilatation may follow causing anaphylactic shock and patient may progress to circulatory failure and death within minutes.

54. Local reaction: depends on the portal of entry of antigen e. g
Local reaction: depends on the portal of entry of antigen e.g. localized cutaneous swelling (skin allergy), nasal and conjunctival discharge (allergic rhinitis and conjunctivitis), bronchial asthma, allergic gastroenteritis ( food allergy).

56. chronic inflammation due to type I hypersensitivity reaction: Nasal mass with edematous stroma with chronic inflammatory cell infiltrate ( mainly eosinophils) covered by ciliated columnar epithelium allergic nasal polyp

57. Bronchial asthma is an example of type I hypersensitivity reaction & is characterized by eosinophilic infiltrate, mucus collection & congestion.