1. IMMUNOLOGICDEFICIENCY SYNDROMES

2. Divided into: Primary immunodeficiency disorders: are almost always genetically determined. Secondary immunodeficiency states: may arise as complications of :- infections; malnutrition; aging; or side effects of immunosuppression, irradiation, or chemotherapy.

3. primary immunodeficiency disorders: X-Linked Agammaglobulinemia of Bruton: characterized by failure of B-cell precursors ( pro-B cells and pre-B cells) to mature into B cells. is due to mutations in a cytoplasmic tyrosine kinase, called B-cell tyrosine kinase (Btk). The BTK gene is found on long arm of X chromosome ( Xq21.22). As X-linked disease, this disorder is seen almost entirely in males.

4. The disease become apparent about age of 6 months. there is recurrent bacterial infections of respiratory tract. Because antibodies are important for neutralizing viruses as well, these patients are also susceptible to certain viral infections. For similar reasons, Giardia lamblia, an intestinal protozoon , that is normally resisted by secreted IgA, causes persistent infections in these patients.

5. The classic form of this disease has the following characteristics :o B cells are absent or markedly decreased in circulation.o serum levels of all classes of immunoglobulins are depressed.o Germinal centers of lymph nodes, Peyer patches, appendix, and tonsils are underdeveloped or rudimentary.o Plasma cells are absent throughout the body.o T cell-mediated reactions are entirely normal. The treatment of X-linked agammaglobulinemia is replacement therapy with immunoglobulins.

6. Common Variable Immunodeficiency : Heterogeneous group of disorders. The feature common to all patients is hypogammaglobulinemia affecting all antibody classes but sometimes only IgG. The diagnosis is based on exclusion of other causes of decreased antibody production. As expected in a heterogeneous group of disorders, both sporadic and inherited forms of disease occur. In inherited forms, there is no single pattern of inheritance.

7. In contrast to X-linked agammaglobulinemia , most patients have normal numbers of mature B cells in blood and lymphoid tissues. These B cells, however, are not able to differentiate into plasma cells, so plasma cells are absent. There are defects in ability of T cells (TH2 ) to send activation signals to B cells. According to others, some patients have intrinsic B-cell defects , as well as abnormalities of T cell-mediated regulation of B cells.

8. The clinical manifestations are caused by antibody deficiency, and hence resemble those of X-linked agammaglobulinemia. affects both sexes equally, and the onset of symptoms is later in childhood or adolescence. Histologically the B-cell areas of lymphoid tissues (lymphoid follicles in nodes, spleen, and gut) are hyperplastic.

9. Isolated IgA Deficiency: extremely low levels of both serum and secretory IgA. It may be familial ( Inherited ); or acquired in association with toxoplasmosis, measles, or other viral infections. Because IgA is major immunoglobulin in external secretions, mucosal defenses are weakened, and infections occur in respiratory, gastrointestinal, and urogenital tracts.

10. The basic defect is in differentiation of naive (un stimulated ) B lymphocytes to IgA-producing cells. Although the molecular basis of this defect is still unknown, intrinsic B cell defects or altered T cell help (TH2 ) have been implicated. In most patients the number of IgA-positive B cells is normal, but only a few of these cells can be differentiated into IgA plasma cells . Serum antibodies to IgA are found in 40% of patients.

11. Hyper-IgM Syndrome : T cell disorder in which functionally abnormal T cells ( TH2 ) fail to induce B cells to make antibodies of isotypes other than IgM . When Naive (unstimulated) B cells stimulated by antigens, IgM and IgD antibodies are produced first, this is followed by sequential formation of IgG, IgA, and IgE antibodies. This normal immune response is called isotype switching. The ability of IgM producing B cells to turn on depends on interaction between CD40 molecules on B cells and CD40L expressed on T cells.

12. In approximately 70% of cases, the mutations affect the gene for CD40L, which maps to Xq26. These patients have X-linked form of disease. In the remaining patients, the mutations affect CD40 , or an enzyme called activation-induced deaminase which is required for isotype switching . The disease in these latter groups of patients is inherited in autosomal recessive pattern.

13. Clinically, patients present with recurrent pyogenic infections because the level of IgG is low. They are also susceptible to pneumonia caused by intracellular organism Pneumocystis carinii, because of defect in cell-mediated immunity. The serum contains normal or elevated levels of IgM, but no IgA or IgE , and extremely low levels of IgG. The number of B and T cells is normal.

14. DiGeorge Syndrome (Thymic Hypoplasia) : Results from failure of development of third and fourth pharyngeal pouches that give rise to thymus , parathyroids , and portions of face and aortic arch. Thus, these patients have a variable loss of T cell-mediated immunity (owing to hypoplasia or lack of thymus) ; tetany (owing to lack of parathyroids) ; and congenital defects of heart and great vessels.

15. Absence of cell-mediated immunity is reflected in poor defense against certain viral , fungal, and protozoal infections. Patients are also susceptible to intracellular bacteria. Immunoglobulin levels may be normal or reduced, depending on severity of T-cell deficiency. In 90% of cases of DiGeorge Syndrome there is deletion affecting chromosome 22q 11.

16. Severe Combined Immunodeficiency Diseases: Defects in both humoral and cell-mediated immune responses. Patients with SCID are extremely susceptible to recurrent, severe infections by a wide range of pathogens, including Candida albicans, P. carinii, Pseudomonas, cytomegalovirus, and bacteria. Without bone marrow transplantation, death occurs within the first year of life. The most common form( 50% to 60% of cases) is X-linked, and hence SCID is more common in boys than in girls.

17. The remaining cases of SCID are inherited as autosomal recessives with deficiency of enzyme adenosine deaminase (ADA). These Mutations prevent development of CD4+ T cells. CD4+ T cells are involved in cellular immunity and provide help to B cells, and hence results in combined immunodeficiency.

18. Immunodeficiency with Thrombocytopenia and Eczema(Wiskott-Aldrich Syndrome): It is X-linked recessive disease ( Xp11.23 ) , characterized by thrombocytopenia, eczema, and recurrent infections, ending in early death. The thymus is morphologically normal, but there is progressive secondary depletion of T lymphocytes in peripheral blood and in T-cell zones (paracortical areas) of lymph nodes, with variable loss of cellular immunity. The only treatment is bone marrow transplantation.

19. Genetic Deficiencies of Complement System: complement system play a critical role in both inflammatory and immunologic responses. Hereditary deficiencies described for all components of complement system and for inhibitors. Hereditary deficiency of C3 : result in increased susceptibility to infection with pyogenic bacteria.

20. Inherited deficiencies of C1, C2 ,and C4 : increase the risk of immune complex- mediated diseases ( e.g, SLE ), possibly by impairing the clearance of Ag-Ab complexes from the circulation. Lack of C1 esterase inhibitor: allow C1 esterase activation with generation of vasoactive mediators that result in hereditory angioedema.

21. Deficiencies of ( C5 to C9 ) : The terminal components of complement [ C5, 6, 7, 8, and 9 ] are required for membrane attack complex , which involved in lysis of organisms ,result in recurrent neisserial ( gonococcal and meningococcal ) infections.

22. THANK YOU