Diseases of Immune System

1. Diseases of Immune System Dr Rehma Dar Assistant professor Pathology

2. Learning Objectives • Introduction to Immune System • Cell mediated vs Humoral Immunity • Hypersensitivity reactions • Autoimmune diseases • Transplant Rejection • Immunodeficiency states

3. The Normal Immune Response The immune system is vital for survival- protects us from infectious pathogens.

4. The mechanisms of protection against infections fall into two broad categories. • Innate immunity • Adaptive immunity

6. Innate immunity • natural, or native immunity refers to defense mechanisms - present even before infection and protect individuals against infections. • first line of defense, because it is always ready to prevent and eradicate infections.

7. Components of innate immunity • epithelial barriers, • phagocytic cells (mainly neutrophils and macrophages), dendritic cells, natural killer (NK) cells, and • several plasma proteins, including complement system.

8. The two most important cellular reactions of innate immunity are: • inflammation, in which phagocytic leukocytes are recruited and activated to kill microbes, and • anti-viral defense, via dendritic cells and NK cells.

9. Leukocytes and epithelial cells recognize components of microbes (called pathogen associated molecular patterns) via cellular receptors. • The recognition receptors are a family of proteins called Toll-like receptors (TLRs)that are homologous to the Drosophila protein Toll. • Different TLRs are specific for components of different bacteria and viruses. • TLRs are located on the cell surface and in endosomes-recognize and initiate cellular responses to extracellular and ingested microbes.

10. Other microbial sensors are located in the cytoplasm -recognize bacteria and viruses that may have colonized cells. • Upon recognition of microbes, the TLRs and other sensors signal by a common pathway - the activation of transcription factors, NF-κB (nuclear factor κB). • NF-κB turns on the production of cytokines and proteins that stimulate the microbicidal activities of phagocytes.

11. Epitheliaof the skin and GITand respiratory tracts - mechanical barriers to the entry of microbes • also produce anti-microbial molecules such as defensins, and lymphocytes located in the epithelia combat microbes at these sites. • Monocytes and neutrophils–phagocytes -rapidly be recruited to any site of infection • Dendritic cellsproduce type I interferons, anti-viral cytokines that inhibit viral infection and replication • Natural killer cells - protection against many viruses and intracellular bacteria

12. Complement system is activated by microbes using the alternative and lectin pathways; in adaptive immunity it is activated by antibodies using the classical pathway. • Other proteins of innate immunity are mannose-binding lectin and C-reactive protein - coat microbes for phagocytosis. • Lung surfactant - provide protection against inhaled microbes.

13. Adaptive immunity • Acquired or specific immunity consists of mechanisms that are stimulated by (“adapt to”) microbes and are capable of recognizing microbial and nonmicrobial substances. • develops later, and is even more powerful than innate immunity in combating infections. • By convention, the term “immune response” refers to adaptive immunity

14. The adaptive immune system consists of lymphocytes and their products, including antibodies. • The receptors of lymphocytes are much more diverse - not inherently specific for microbes, and they are capable of recognizing a vast array of foreign substances.

15. There are two types of adaptive immunity: • Humoral immunity • Cell-mediatedimmunity

16. Humoral immunity - protects against extracellular microbes and their toxins, • mediated by B (bone marrow–derived) lymphocytes and their secreted products, antibodies (also called immunoglobulins, Ig) • Cell-mediatedimmunity- responsible for defense against intracellular microbes, • mediated by T (thymus-derived) lymphocytes. • Both classes of lymphocytes express highly specific receptors for a wide variety of substances, called antigens.

18. Lymphocytes • appear morphologically similar – heterogeneous • Mature lymphocytes that have not encountered specific antigen - naive(immunologically inexperienced). • activated by recognition of antigens - differentiate into effector cells, which perform the function of eliminating microbes, and • memory cells, better able to combat the microbe in case it returns

19. Lymphocytes • T Lymphocytes • B Lymphocytes • NK cells

20. T lymphocytes • develop from precursors in the thymus. • constitute 60% to 70% of blood lymphocytes and in T-cell zones of peripheral lymphoid organs (paracortical & medullary) • Each T cell recognizes a specific cell-bound antigen by means of an antigen-specific T-cell receptor (TCR).

22. TCR recognizes peptide antigens that are displayed by major histocompatibility complex (MHC) molecules on the surfaces of antigen-presenting cells (APCs). • CD4+ T cells (Helper) :60% of T lymphocytes • CD8+ T cells (Cytotoxic): 30% of T lymphocytes • Normal 2:1 (CD4+ : CD8+)

24. TCR disulfide-linked α and a β polypeptide chain having a variable (antigen-binding) region and a constant region. • TCR diversity - somatic rearrangement of the genes that encode the TCR α and β chains • Each TCR linked to CD3 complex -transduction of signals into the T cell after the TCR has bound the antigen • T cells express CD4, CD8, CD2, integrins, and CD28 -assist the functional responses.

25. B Lymphocytes • develop from precursors in the bone marrow. • constitute 10% to 20% of the circulating lymphocyte and also present in peripheral lymphoid tissues like lymph nodes(germinal centers), spleen, and mucosa-associated lymphoid tissues. • recognize antigen via the B-cell antigen receptor complex.

26. Membrane-bound antibodies called IgM and IgD, present on the surface of all mature, naive B cells, are the antigen-binding component of the B-cell receptor complex • After stimulation - B cells - plasma cells that secrete antibodies, the mediators of humoral immunity. • B cells also express complement receptors, Fc receptors, and CD40- essential for their responses.

28. Natural Killer Cells • 10% to 15% of peripheral blood lymphocytes. • do not express TCRs or Ig. • contain abundant azurophilic granules; because of these characteristics, they are also called large granular lymphocytes. • early line of defense against viral infections and some tumors • Neither prior sensitization nor Ab is involved in killing • secrete cytokines, such as interferon-γ (IFN-activates macrophages to destroy ingested microbes- intracellular microbial infections.

30. Dendritic Cells • numerous fine cytoplasmic processes that resemble dendrites • the most important antigen-presenting cells (APCs) for initiating primary T-cell responses • Located under epithelia, the common site of entry of microbes and foreign antigens, and in the interstitia of all tissues, where antigens may be produced. • Immature dendritic cells within the epidermis are called Langerhans cells. • express many receptors for capturing and responding to microbes

32. Macrophages • part of the mononuclear phagocyte • phagocytosed microbes and protein antigens process the antigens and present peptide fragments to T cells. - function as APCs in T-cell activation.( MHC II to CD4+) • key effector cells in certain forms of cell-mediated immunity, the reaction that serves to eliminate intracellular microbes. • also participate in the effector phase of humoral immunity-phagocytose and destroy microbes opsonized (coated) by IgG or C3b.

33. Tissues of the Immune System • Generative Lymphoid Organs also called primary, or central • Peripheral Lymphoid Organs or secondary

34. Generative Lymphoid Organs • in which T and B lymphocytes mature and become competent to respond to antigens • thymus, where T cells develop, and the bone marrow, where B lymphocytes mature. Peripheral Lymphoid Organs • in which adaptive immune responses to microbes are initiated. • lymph nodes, spleen, and the mucosal and cutaneous lymphoid tissues.

35. Human Leukocyte Antigen(HLA) system & Major Histocompatibility Complex(MHC) • HLA system – group of related proteins called as HLA antigens. • Genes that code for HLA are called histocompatibility genes. • responsible for tissue compatibility between individuals. • The physiologic function of MHC molecules is to display peptide fragments of proteins for recognition by antigen-specific T cells

36. genes encoding the major histocompatibility molecules are clustered on a small segment of chromosome 6, the major histocompatibility complex, or the human leukocyte antigen (HLA) complex

40. fundamental to the recognition of antigens by T cells and are linked to many autoimmune diseases • evoke rejection of transplanted organs, • are responsible for tissue compatibility between individuals. • highly polymorphic, - many alleles of each MHC gene in the population and each individual inherits one set of these alleles that is different from the alleles in most other individuals.

41. On the basis of their structure, cellular distribution, and function, MHC gene products are classified into three groups. • • Class I MHC moleculesare expressed on all nucleated cells and platelets except RBC • They are encoded by three closely linked loci, designated HLA-A, HLA-B, and HLA-C

42. Since CD8+ T cells recognize peptides only if presented as a complex with self–class I MHC molecules, CD8+ T cells are said to be class I MHC–restricted. • Because one of the important functions of CD8+ CTLs is to eliminate viruses, which may infect any nucleated cell- nucleated cells express class I HLA molecules and can be surveyed by CD8+ T cells.

43. Class II MHC moleculesare encoded in a region called HLA-D, which has three subregions: HLA-DP, HLA-DQ, and HLA-DR. • The class II - binding site for CD4, and , the class II–peptide complex is recognized by CD4+ T cells, which function as helper cells- they are referred to as class II MHC–restricted. • mainly expressed on cells that present ingested antigens and respond to T-cell help (macrophages, B lymphocytes, and dendritic cells).

44. Class III MHC molecules -MHC locus also contains genes - encode some complement components and the cytokines tumor necrosis factor (TNF) and lymphotoxin • contains genes that encode many proteins involved in antigen processing and presentation

46. Antigen processing and display by major histocompatibility complex (MHC) molecules

47. MHC molecules play key roles in regulating T cell–mediated immune responses • MHC molecules ensure that the correct immune response is mounted against different microbes— • CD8+ T against cytoplasmic microbes, and • antibodies and macrophages (both of which are activated by CD4+helper T cells) against extracellular microbes.

48. HLA and Disease Association • A variety of diseases are associated with the inheritance of certain HLA alleles • The most striking is the association between ankylosing spondylitis and HLA-B27; • individuals who inherit this class I HLA allele have a 90-fold greater chance (relative risk) of developing the disease as compared with those who do not carry HLA-B27.

49. The diseases that show association with the HLA locus can be broadly grouped into the following categories: • 1. Inflammatory diseases, including ankylosing spondylitis and several post-infectious arthropathies, all associated with HLA-B27 • 2. Autoimmune diseases, including autoimmune endocrinopathies, associated mainly with alleles at the DR locus • 3. Inherited errors of metabolism, such as 21-hydroxylase deficiency (HLA-BW47) and hereditary hemochromatosis (HLA-A)