Diseases of Immune System

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

2. TRANSPLANTATION

9. Rejection of Tissue Transplants • A major barrier to transplantation is the process of rejection, in which the recipient's immune system recognizes the graft as being foreign and attacks it. • Mechanisms of Recognition and Rejection of Allografts Rejection is a complex process – both • cell-mediated immunity and • circulating antibodies

10. T Cell–Mediated Reactions • called cellular rejection, and • it involves destruction of graft cells by CD8+ CTLs and delayed hypersensitivity by activated CD4+ helper cells. • The major antigenic differences between a donor and recipient - rejection of transplants -differences in highly polymorphic HLA alleles. • The recipient's T cells recognize donor antigens from the graft by two pathways, called • Direct • indirect

11. Direct pathway • T cells of the transplant recipient recognize allogeneic (donor) MHC molecules on the surface of APCs( dendritic cells) in the graft. • APCs express class I and II MHC and costimulatory molecules (e.g., B7-1 and B7-2). • The T cells of the host encounter the donor dendritic cells within the grafted organ or after the dendritic cells migrate to the draining lymph nodes.

12. CD8+ T cells recognize class I MHC mdecules and differentiate - active CTLs- kill the graft cells • CD4+ helper T cells recognize allogeneic class II molecules - differentiate into TH1 (and possibly TH17) effector cells • Cytokines secreted trigger a delayed hypersensitivity reaction in the graft injury caused by the activated macrophages.

14. Indirect pathway • recipient T lymphocytes recognize MHC antigens of the graft donor - presented by the recipient's own APCs. • uptake and processing of MHC and other foreign molecules from the grafted organ by host APCs • CD4+ T recognize graft - delayed hypersensitivity type of reaction. • However, CD8+ CTLs cannot directly recognize or kill graft cells, - graft antigens presented by the host's APCs.

15. indirect pathway, the principal mechanism - delayed hypersensitivity. • Direct pathway - acute cellular rejection • Indirect pathway - chronic rejection.

18. Antibody-Mediated Reactions • Humoral rejection - Antibodies produced against alloantigens in the graft • Hyperacute rejection - preformed antidonor antibodies are present in the circulation of the recipient. • Such antibodies -previously rejected a kidney transplant. • Multiparous women develop anti-HLA antibodies against paternal antigens shed from the • blood transfusions can also lead to presensitization, because platelets and white blood cells are rich in HLA antigens • cross-matching, - testing recipient's serum for antibodies against donor's cells, hyperacute rejection is no longer a significant clinical problem.

19. Acute humoral rejection • In recipients not previously sensitized to transplantation antigens, exposure to the class I and class II HLA antigens of the donor graft - antibodies. • The antibodies formed by the recipient may cause injury • complement-dependent cytotoxicity, inflammation, and antibody-dependent cell-mediated cytotoxicity. • The initial target of these antibodies in rejection seems to be the graft vasculature- vasculitis

24. within days of transplantation in the untreated recipient or months or even years later, after immunosuppression terminated. • cellular or humoral immune mechanisms may predominate. • humoral rejection -vasculitis, whereas • cellular rejection -interstitial mononuclear cell infiltrate

28. Transplantation of Hematopoietic Cells • Two problems that are unique to bone marrow transplantation are • graft-versus-host (GVH) disease • immunodeficiency

30. GVHD • immunologically competent cells or their precursors are transplanted into immunologically crippled recipients, and the transferred cells recognize alloantigens in the host. • In immune-compromised, the immunocompetent T cells present in the donor marrow recognize the recipient's HLA antigens as foreign and react against them.

32. Acute GVH disease • occurs within days to weeks • clinical manifestations - involvement of the immune system and epithelia of the skin, liver, and intestines. • Involvement of skin in GVH disease is manifested by a generalized rash –desquamation • Destruction of bile ducts –jaundice • mucosal ulceration of the gut - bloody diarrhea.

33. affected tissues are not infiltrated by lymphocytes. • cytotoxicity by CD8+ T cells • cytokines released by the sensitized donor T cells

34. Chronic GVH disease • Insidiously • extensive cutaneous injury, fibrosis of the dermis. • Chronic liver disease -cholestatic jaundice • Damage to the gastrointestinal tract -esophageal strictures. • The immune system is devastated, with involution of the thymus and depletion of lymphocytes in the lymph nodes. • recurrent and life-threatening infections. • Autoimmunity- grafted CD4+ helper T cells reacting with host B cells -autoantibodies

36. Immunodeficiency • frequent complication of bone marrow transplantation. • result of prior treatment, myeloablative preparation for the graft • attack on the host's immune cells by grafted lymphocytes. • infection with cytomegalovirus -induced pneumonitis can be a fatal complication.

37. IMMUNODEFICIENCY

38. It is the absence or failure of normal function of one or more elements of the immune system • Results in immunodeficiency disease • Can be specific or non specific Specific = Abnormalities of B & T cells Non specefic = Abnormalities of non specific components PRIMARY OR SECONDARY

39. Immunodeficiency Syndromes • Primary immunodeficiency disorders- always genetically determined • Secondary immunodeficiency disorders - arise as complications of cancers, infections, malnutrition, or side effects of immunosuppression, irradiation, or chemotherapy for cancer and other diseases.

40. PRIMARY IMMUNODEFICIENCIES • Humoral and/or cellular - adaptive immunity • Defense mechanisms of innate immunity (NK cells, phagocytes, or complement). • Defects subclassified on the basis of the primary component involved (i.e., B cells or T cells or both) • distinctions are not clear-cut • Most primary immunodeficiencies manifest themselves in infancy, between 6 months and 2 years of life- detected -infants are susceptible to recurrent infections.

41. B CELL DEFICIENCY • X liked a gammaglobuinemia • IgA deficiency • IgG subclass deficiency • Immunodeficiency with increased Igm • Common variable immundeficiency • Transient hypogammaglobulinaemia of infancy

42. X-linked a gammaglobulinaemia(Bruton'sAgammaglobulinemia) • Most common form • maturation of B cells fails • Affect males • mutations in a cytoplasmic tyrosine kinase, called Bruton tyrosine kinase (Btk) • Few or no B cells in blood & No Ig • The disease usually does not become apparent until about 6 months of age- maternal immunoglobulins are depleted. • Very small lymph nodes and tonsils • Recurrent pyogenic infection

43. Common Variable Immunodeficiency (CVID) • relatively common • Hypogammaglobulinemi- all the antibody classes - sometimes only IgG. • normal or near-normal numbers of B cells • Recurrent pyogenic & viral infection • affects both sexes equally • lymphoid tissues are hyperplastic – absence of normal feedback inhibition

44. intrinsic B-cell defects and abnormalities in T helper cell–mediated activation of B cells • abnormality is in a receptor for a cytokine called BAFF -survival and differentiation of B cells, or • in a molecule called ICOS (inducible costimulator) involved in T-cell activation & interactions between T and B cells

45. IsolatedIgA • Common (1 in 600 individuals of European descent in US) • low levels of both serum and secretoryIgA • familial, or acquired in association with toxoplasmosis, measles, or other viral infection • Symptomatic patients commonly present with recurrent sinopulmonary infections and diarrhea • have a high frequency of respiratory tract allergy

46. Hyper-IgM Syndrome (HIgM) • deficient in their ability to produce IgG, IgA, and IgE antibodies • Production of large amount of IgM • Formation of IgM to neutrophils, platelets and other blood components- autoimmune hemolytic anemia, thrombocytopenia, and neutropenia • recurrent pyogenic infections, because the level of opsonizingIgG antibodies is low • X-linked form OR autosomal recessive

47. mutations in the gene encoding CD40 or the enzyme called activation-induced deaminase, a DNA-editing cytosine deaminase required for class switching and affinity maturation

48. DISORDERS of T CELLS • DiGeorge's syndrome: • results from failure of development of the third and fourth pharyngeal pouches. • Also known as congenital thymicaplasia/hypoplasia • loss of T cell–mediated immunity • Associated with hypoparathyroidism (tetany) congenital heart disease, fish shaped mouth (hypoparathyroidism s), and congenital defects of the heart and great vessels. • In addition, the appearance of the mouth, ears, and facies may be abnormal.

49. SEVERE COMBINED IMMUNODEFICENCY • common defects in both humoral and cell-mediated immune responses (absence (or very low numbers of circulating T and B lymphocytes) • Affected infants present with prominent thrush (oral candidiasis), extensive diaper rash, and failure to thrive. • extremely susceptible to recurrent, severe infections by a wide range of pathogens • - autosomal recessive • defect resides in the T-cell compartment, with a secondary impairment of humoral immunity.

50. The X-linked - defect in in the commonγ-chain (γc) subunit of cytokine receptors(IL-2, IL-4, IL-7, IL-9, IL-11, IL-15, and IL-21. IL-7) involved in lymphocyte proliferation andrdifferentiation. • The autosomal- from defects in adenosine deaminase(ADA) accumulation of dATP - toxicity to dividing immature lymphocytes