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1. IMMUNODEFICIENCIES Deo Okoche

2. I mmune system is subject to failure of some or all of its parts, like any multi-component system When the system loses its sense of self and begins to attack host cells and tissues, it results into Autoimmunity When the system fails to protect the host from disease-causing agents or malignant cells, the result is immunodeficiency I ndividuals with severe immunodeficiency are at risk of infection with opportunistic agents M icroorganisms that healthy individuals can harbor with no ill consequences but cause disease in those with impaired immune function

3. Types of Immunodeficiency Primary immunodeficiency A condition resulting from a genetic or developmental defect in the immune system T he defect is present at birth although it may not manifest itself until later in life Secondary immunodeficiency/acquired immunodeficiency I nvolves loss of immune function and results from exposure to various agents T he most common example is acquired immunodeficiency syndrome (AIDS) resulting from HIV

4. Primary Immunodeficiencies M ay affect either adaptive or innate immune functions The two main cell lineages important to immune function are lymphoid and myeloid The lymphoid cell disorders may affect T cells, B cells or in combined immunodeficiencies , both B and T cells M yeloid cell disorders affect phagocytic function Most of the primary immunodeficiencies are inherited Other i mmunodeficiencies stem from developmental defects that impair proper function of an organ of the immune system

5. Primary Lymphoid Immunodeficiencies The combined forms of this deficiency affect both lineages & are lethal within the first few years of life B-cell immunodeficiency disorders make up a diverse spectrum of diseases; C omplete absence of mature recirculating B cells, plasma B cells, and selective absence of only certain immunoglobulins classes Patients are subject to recurrent infections with extracellular bacterial but display normal immunity to most viral, intracellular bacteria and fungal infections, because the T-cell is largely unaffected

6. T-cell deficiency can affect both the humoral and the cell-mediated responses T cells play a central role in the immune system (including requirement for T H cells in B-cell activation) Reduces both delayed-type hypersensitive responses and cell-mediated cytotoxicity I ncreased susceptibility to viral, protozoan, fungal and intracellular bacterial infections

7. Examples of Lymphoid Immunodeficiencies Severe Combined Immunodeficiency (SCID) Wiskott -Aldrich Syndrome (WAS) X-linked agammaglobulinemia X-linked hyper- IgM syndrome Common Variable Immunodeficiency (CVI) Hyper- IgE Syndrome (Job Syndrome) Ataxia telangiectasia Immune disorders involving the thymus

8. Severe Combined Immunodeficiency (SCID) SCID stems from defects in lymphoid dev’t that affect either T cells or both T & B cells Clinically is x terized by a very low number of circulating lymphocytes There is a failure to mount immune responses mediated by T cells The thymus does not develop , & few circulating T cells don’t respond to stimulation by mitogens, indicating that they cannot proliferate in response to antigens

9. Myeloid & erythroid cells appear normal in number & function, indicating that only lymphoid cells are depleted in SCID Very fatal in early years of life The initial manifestation of SCID in infants is infection by agents, like fungi or viruses, normally dealt with by T-cell immunity B-cell defect is not evident in the first few months of the affected infant’s life due to antibodies from the mother

10. SCID infants suffer from chronic diarrhea, pneumonia, and skin, mouth, throat lesions and other opportunistic infections The immune system is so compromised that even live attenuated vaccine e.g polio vaccine, can cause infection The life span of a patient can be prolonged by preventing contact with all potentially harmful microorganisms pending treatment

11. D efects that cause SCID Defects in thymic development Deficiency of the common gamma chain of the IL-2 receptor (IL-2Rγ) This prevents signaling through receptors for IL-4, -7, -9, and -15 as well as the IL-2 receptor Deficiency in the kinase JAK-3 prevents signal transduction ADA (Adenosine deaminase ) and Purine nucleoside phosphorylase (PNP) deficiency; ADA & PNP catalyze conversion of adenosine to inosine , and its deficiency results in accumulation of adenosine, which interferes with purine metabolism and DNA synthesis

12. Deficiency of tyrosine kinase ZAP-70, an important element in T-cell signal transduction . This leads to depletion of CD8 + T cells Patients may have normal levels of immunoglobulins and CD4 + lymphocytes, but their CD4 + T cells are non-functional A defect in the genes that encode mediators of the rearrangement processes (recombination-activating proteins RAG-1 and RAG-2) Leads to dev’t of non-functional receptors of B and T cells Defect that leads to failure to transcribe the genes that encode class II MHC molecules P atient’s lymphocytes can’t participate in cellular interactions with T H cells

13. Lack of class I MHC molecules Due to mutation in the TAP genes that are vital to antigen processing and presentation by class I MHC molecules Impairs CD8 cell response hence susceptibility to infection by intracellular pathogens Treatment of SCID Thymic graft Gene therapy (* promising ) Bone marrow transplant

14. Wiskott -Aldrich Syndrome (WAS) The severity of this X-linked disorder increases with age & results in fatal infection or lymphoid malignancy Initially, T and B lymphocytes are present in normal numbers M anifests itself by defective responses to bacterial polysaccharides and by lower-than-average IgM levels As patient ages ; recurrent bacterial infections and a gradual loss of humoral and cellular responses The syndrome includes; Thrombocytopenia (lowered platelet count). Platelets are too small with short lifespan-Fatal bleeding may occur Eczema (skin rashes); may occur at the beginning at age of 1yr

15. Defect mapped to be in genes of short arm of X-chromosome Involves deficiency in a cytoskeletal glycoprotein present in lymphoid cells called sialophorin (CD43) This protein is required for assembly of actin filaments required for the formation of microvesicles Treatment : Gene therapy

16. X-linked agammaglobulinemia (XLA) Also called Bruton’s hypogammaglobulinemia It’s B-cell defect Xterized by extremely low IgG levels & absence of other Ig classes XLA individuals have no peripheral B cells and suffer from recurrent bacterial infections, beginning at about 9months of age Also have defect in B-cell signal transduction in due to a defect in a transduction molecule Bruton’s tyrosine kinase ( Btk )

17. Their B cells remain in the pre-B stage with H chains rearranged but L chains in their germ-line configuration Treatment Lifetime infusion of antibodies

18. X-linked hyper- IgM syndrome (XHM) XHM syndrome is inherited as an X-linked recessive disorder due to defect in T cell surface molecule Xterised by a deficiency of IgG , IgA , and IgE , and elevated levels of IgM Patients have normal numbers of B cells expressing membrane-bound IgM or IgD but not IgG , IgA , or IgE In addition, patients often have high levels of auto-antibodies to neutrophils, platelets, and RBCs The defect in XHM is in the gene encoding the CD40 ligand (CD40L) T H cells from patients fail to express functional CD40L on their membrane

19. An interaction between CD40 on the B cell and CD40L on the T H cell is required for B-cell activation, The absence of this co-stimulatory signal (CD40 L) inhibits the B-cell response to T-dependent antigens Absence CD40-CD40L interaction results in the loss of class switching to IgG , IgA , or IgE isotypes and in a failure to produce memory B cells B-cell response to T-independent antigens is unaffected leading to prodn of IgM antibodies hence its high levels Treatment : Lifetime infusion of missing antibodies ( IgG , IgA or IgE ), antiglobulins against autoantibodies

20. Common Variable Immunodeficiency (CVI) CVI is characterized by; A profound decrease in numbers of antibody-producing plasma cells, Low levels of most immunoglobulin isotypes ( hypogammaglobulinemia ) Recurrent bacterial infections which can be controlled by administering different classes of antibodies Defect not known but may involve; An in vivo blockage of the maturation of B cells to the plasma-cell stage, or T heir inability to produce the secreted form of Igs

21. Hyper- IgE Syndrome (Job Syndrome) A primary immunodeficiency characterized by; Skin abcesses Recurrent pneumonia and eczema Elevated levels of IgE accompanies facial abnormalities and bone fragility Eosinophilia This multi-system disorder is autosomal dominant The gene for hyper IgE syndrome maps to chromosome 4 in humans Treatment : administering antibodies against IgE to lower IgE levels, gene therapy

22. Ataxia telangiectasia Ataxia telangiectasia is a disease syndrome that includes deficiency of IgA and sometimes of IgE It is characterized by difficulty in maintaining balance (ataxia) & by the appearance of broken capillaries (telangiectasia) in the eyes The primary defect appears to be in a kinase involved in regulation of the cell cycle The r/ship betn the immune deficiency and the other defects in ataxia telangiectasia is unknown Treatment : lifetime infusion of IgA or IgE

23. Immune disorders involving the thymus DiGeorge syndrome (congenital thymic aplasia ), in its most severe form is the complete absence of a thymus This dev’tal defect is associated with the deletion in the embryo of a region on chromosome 22 Causes immunodeficiency along with xteristic facial abnormalities, hypoparathyroidism , and congenital heart disease

24. The immune defect includes a profound decrease of T-cell numbers & absence of T-cell responses B cells are present in normal numbers but do not produce antibodies Affected individuals suffer from chronic diarrhea, viral and fungal infection Treatment : thymic graft

25. Some primary human immunodeficiency diseases and underlying genetic defects

26. Murphy et al. 9 th edition ATM , ataxia telangiectasia mutated protein; SAP, signaling lym ­ phocyte activation molecule (SLAM ) ­ asso ciated protein], or the X linked inhibitor of apoptosis gene ( XIAP).

27. Myeloid Immunodeficiencies Defects in the myeloid cell lineage affect the innate immune functions Most of these defects result in impaired phagocytic processes; Manifested by recurrent microbial infection of greater or lesser severity Myeloid deficiencies include; Reduction in neutrophil count Chronic Granulomatous Disease (CGD) Chediak -Higashi syndrome Leukocyte Adhesion Deficiency (LAD )

28. Reduction in neutrophil count Neutrophils are circulating granulocytes with phagocytic function Neutropenia (low neutrophil count) Congenital neutropenia is caused by a genetic defect that affects the myeloid progenitor stem cell It results in reduced production of neutrophils during hematopoiesis Myeloid stem cells are present in the bone marrow but rarely differentiate beyond the promyelocyte stage The children suffer from frequent bacterial infections

29. This genetic defect results in decreased prodn of granulocyte colony stimulating factor (G-CSF) and Thus in a failure of the myeloid stem cell to differentiate along the granulocytic lineage Treatment: Use of antibiotics to control frequent bacterial infections

30. Chronic Granulomatous Disease (CGD) CGD is a genetic disease of two forms; X-linked form that occurs in about 70% of patients An autosomal recessive form found in the rest This disease is due to a defect in the oxidative pathway B y which phagocytes generate H 2 O 2 & resulting reactive species, e.g ; hypochlorous acid, that kill phagocytosed bacteria Patients; Have excessive inflammatory reactions result in gingivitis , swollen lymph nodes, and nonmalignant granulomas Susceptible to bacterial and fungal infection

31. Resistant to bacteria like pneumococcus, that generate their own hydrogen peroxide Myeloperoxidase in the host cell can use the bacterial hydrogen peroxide to generate hypochlorous acid Other defects of CGD; Missing/defective cytochrome ( cyt b558) that functions in an oxidative pathway Defects in phagocyte oxidases ( phox ) that stabilize the cytochrome In addition, there is decrease in the ability of mononuclear cells to serve as APCs Treatment: Bone marrow transplant Gene therapy Use antibiotics & antifungals

32. Chediak -Higashi syndrome This autosomal recessive disease is xterized by; Recurrent bacterial infections, partial oculo-cutaneous albinism (lack of skin and eye pigment), and Aggressive but nonmalignant infiltration of organs by lymphoid cell Phagocytes from patients contain giant granules but do not have the ability to kill bacteria The defect is a mutation in a protein (LYST) involved in the regulation of intracellular trafficking

33. The mutation impairs the targeting of proteins to secretory lysosomes, which makes them unable to lyse bacteria Treatment : Bone marrow transplant U sing antibiotics to treat bacterial infections

34. Leukocyte Adhesion Deficiency (LAD) Source: Kuby Immunology

35. General Treatment Replacement of a missing protein Replacement of a missing cell type or lineage Replacement of a missing or defective gene (gene therapy)

36. Defects in complement & regulatory proteins Murphy et al. 9 th edition

37. ACQUIRED IMMUNODEFICIENCIES Acquired hypogammaglobulinemia Patients generally have very low but detectable levels of total immunoglobulin Patients have recurrent infection which manifests itself in young adults Cause unknown

38. Agent-induced immunodeficiency Results from exposure to any of a number of chemical and biological agents that induce an immunodeficiency Corticosteroids; used for autoimmune disorders, interfere with the immune response in order to relieve disease symptoms Deliberately induced in transplantation patients They are given immunosuppressive drugs like cyclosporin A, to blunt the attack by immune system on transplanted organs

39. Cytotoxic drugs or radiation treatments given to treat various forms of cancer Cause damage to the dividing cells in the body, including those of the immune system Induce a state of immunodeficiency as an unwanted consequence Patients with such therapy must be monitored closely and treated with antibiotics or immunoglobulin if infection appear

40. Acquired Immunodeficiency syndrome (AIDS) It is a severe immunodeficiency caused human immunodeficiency virus (HIV) It is xterised by; A marked deficiency in cellular immune responses A significant decrease in the subpopulation of T cells that carry the CD4 marker (T helper cells) Treatment : Using antiviral agents to limit viral replication in order to reduce the number of infected & destroyed CD4 T cells This allows CD4 T cells to increase in number

41. Thanks