Immune deficiency syndromes

1. Immune deficiency syndromes Keri C. Smith May 28, 2009

2. Immune deficiencies • Primary • Hereditary or acquired • Can be categorized based on clinical presentation • Cell mediated (T cell) • Antibody mediated (B cell) • Nonspecific (phagocytes, NK cells) • Complement activation • Secondary • Immune deficiency is the result of another disease

3. Major clinical manifestations of immune disorders

4. Severe Combined Immunodeficiency Disease (SCID) • Life threatening infections soon after birth • Wasting, Failure to thrive • Lack of Thymic shadow • Lack of CD3+, CD4+, CD8+ and lymphocyte response to antigens

5. “The Boy in the Bubble”

6. Primary immunodeficiencies • Severe Combined Immunodeficiency Disease • T-B+ • X-linked SCID (40-50% of cases) • Lack g chain for common cytokine receptor • Autosomal recessive SCID • Mutation in gene that encodes JAK3 tyrosine kinase

7. X linked and autosomal recessive

8. Primary immunodeficiency • Severe Combined Immunodeficiency Disease • T-B- • Adenosine deaminase deficiency (20% of cases) • Missing housekeeping enzyme in purine salvage pathway, autosomal recessive, buildup of toxic wastes affects B and T cells • Purine nucleoside phosphorylase deficiency • Purine salvage pathway, toxic wastes affect neurologic system and T cells (these patients have autoimmunity?!) • Recombinase deficiency • RAG 1 and 2 required for the rearrangement of Ig genes and TCR. Cells are stuck in pre-B and pre-T stages. NK cell function OK

9. Primary Immunodeficiency • Severe Combined Immunodeficiency Disease • T+B- • Omenn syndrome • “leaky” SCID with partial RAG activity. Th2 imbalance and a tendency towards hyper IgE syndrome • T+B+ • Bare lymphocyte syndrome • Failure to express HLA molecules • ZAP-70 mutation • Unable to signal through TCR

10. Failure to stimulate T cells

11. Multisystem disorders • Wiskott-Aldrich Syndrome • X linked mutation in gene encoding protein that interacts with cytoskeleton • Bleeding, recurrent bacterial infections, allergic reactions • Abnormal B and T cells, low T cell count • Can be treated with antibiotics, antivirals, bone marrow transplant • Ataxia Telangiectasia • Mutation in ATM gene • Manifests as staggering gait with abnormal vascular dilation • Increased susceptibility to infection, lymphopenia, depressed Ig and T cell response

12. Treatment for SCID • Bone marrow/ placental stem cell transplant • IvIg if necessary • Supportive care • Gene therapy, if possible • Avoid live viral vaccines! • CMV-/irradiated/low WBC blood transfusions

13. Future research directions…. Careful consideration of patients Different vectors? Monitor patients for insertion sites Stem cells?

14. Immunodeficiencies of T cells and cell -mediated immunity • Patients are susceptible to viral, fungal, and protozoal infections • Often exhibit selective defects in Ab production • Can be difficult to distinguish from SCID patients

15. DiGeorge syndrome • Congenital thymic aplasia – thymus does not develop normally (neither does parathyroid) 1:4000 • Results from deletion in chromosome 22q11, but is not inherited • Few to no mature T cells in periphery • Symptoms: • Hypocalcemia • Congenital cardiac disease • Recurrent or chronic infections with viruses, bacteria, fungi, protozoa • Lack of immune response after immunization with T dependent antigens

16. Former treatment of DiGeorge syndrome • Fetal thymus graft (<14 weeks gestation) • Why did this result in functional T cells? Donor fetal thymus provided thymic epithelial cells, and patient’s T cells had an environment to mature • Why did the T cells “collaborate” poorly with patient APC? Patient T cells recognized the MHC of the donor as “self”, not the patient MHC.

17. Nude Mice • Mouse model for DiGeorge syndrome

18. T cell deficiencies with normal peripheral T cell numbers • Functional, rather than numerical defect in T cell population • Susceptible to opportunistic infections, high incidence of autoimmune disease • Autosomal recessive • Deficient expression in: • ZAP-70 tyrosine kinase (phenotype includes CD8 deficiency and SCID-like symptoms • CD3e • CD3g

19. ALPS • Autoimmune Lymphoproliferative Disorder • Systemic autoimmune disease, susceptible only to chronic viral infections • Increased CD4-/CD8- T cells, can develop B cell lymphomas • Most patients have a mutation in gene encoding for Fas (CD95)

20. Chronic Mucocutaneous Candidiasis • Poorly defined collection of syndromes characterized by Candida infections of skin and mucous membranes • Normal B cell immunity, and normal T cell immunity (to everything other than Candida) • May be inherited, affects predominantly children

21. B cell or Ig-associated Immunodeficiency • May be associated with defective B cell development (absence of all Ig subclasses) or deficiency in subclass or class of Ig • Patients suffer from recurrent or chronic infections

22. Brunton’s agammaglobulinemia • X-linked infantile agmmaglobulinemia • 1:100,000 • Noticed in infants at 5-6 months of age • Serious and repeated bacterial infections • Defect in BTK gene • Pre-B cells cannot develop into mature B cells • Treatment consists of IvIg injections, but chronic lung disease is a problem

23. Transient Hypogammaglobulinemia • Normal number of B cells in blood • Transient inability to produce IgG • May be due to deficiency in number and function of helper T cells • Does not usually persist past 2 years

24. CVID • Common Variable Immunodeficiency Disease • Onset 15-35 years, decreased serum IgA, IgG, low to normal IgM • Pneumonia, bronchiectasis, sinusitis, GI infections • May also have autoantibodies, SLE, higher incidence of cancer • Caused by failure of B cells to mature to Ab secreting cells • Class II MHC 6th chromosome • ICOS gene (5%) • TACI gene (15%) • Treatment with IvIg

26. IgA deficiency • 1:800 incidence • Lack of serum and mucosal IgA • Usually asymptomatic • GI, respiratory disease • Associated with allergy, autoimmunity • Etiology unknown, but familial associations and linkage with CVID • Broad spectrum antibiotics

27. Association between CVID and IgAD

28. Patients with IgA deficiency are usually treated with broad-spectrum antibiotics. Why is the injection of IgA not a suitable treatment in these patients? • Serum sickness will occur • IgA isn’t a good activator of complement, and thus is useless against bacterial infections • Injected IgA is unlikely to be secreted at the mucosal immune surfaces • A,B,and C • A and C

29. Treatment of Ig deficiency disorders • IvIg • Supportive care (antibiotics) • No live viral vaccines! • Complications include malignancies, autoimmunity

30. Hyper IgM syndrome • Mostly males, rarely females • Severe respiratory infections, sinusitis, diagnosed age 1-2 • Very low serum IgG, IgE, IgA, and normal to elevated IgM • T cell immunity can weaken with time • Abnormal germinal center formation • Complications include malignancy, autoimmunity

31. The many causes of Hyper IgM

35. Duncan Syndrome • X-linked lymphoproliferative disease • Originally observed in 6 maternally related males of the Duncan family • T cells can’t regulate B cell growth • Exposure to EBV results in severe infectious mononucleosis • High probability of lymphoma development • Poor prognosis

36. Phagocytic dysfunctions • Affect the innate and acquired response to pathogens • Dysfunction in: • Action required to phagocytize • Migration and adhesion of phagocytic cells

37. LAD • Leukocyte adhesion deficiency • Autosomal recessive • Group of disorders in which the leukocyte interaction with vascular endothelium is disrupted • b subunit of integrins • Selectin ligands • Consequences: • Recurrent soft tissue bacterial infection • Increased blood WBC counts • No pus formation or effective wound healing

38. BLAD • Early 1990’s – up to 15% of Holstein bulls and 6-8% of cows were carriers for mutated CD18 gene • Up to 20,000 calves/year potentially affected • Screening for the affected gene reduced incidence

39. Chediak-Higashi Syndrome • Autosomal recessive • Abnormal giant granules and organelles in the cell • Diminished killing of intracellular organisms (lysosomes and degranulation), leading to massive infiltration of lymphocytes and macrophages in liver, spleen, lymph nodes • Strep and Staph main problem – recurrent infections • Poor prognosis

40. Chronic Granulomatous Disease • X-linked, autosomal recessive • Skin, lymph node, lung infections • High WBC in blood • Phagocytes unable to complete respiratory burst • Treatments include antibiotics, antifungals, IFNg

41. Summary of phagocytic dysfunction

42. Complement Abnormalities • Deficiencies inherited in autosomal fashion, heterozygotes have 50% of given complement protein • Complement is required for: • Opsonization and killing of bacteria • Chemotaxis • B cell activation • Elimination of Ag-Ab complexes

43. Early complement protein deficiencies • C1, C2, C4 or C3 deficiency • Pyogenic infections • Autoimmunity – SLE very common

44. Late complement protein deficiencies • C5-C9 • Prevents formation of membrane attack complex • Gram negative bacterial infections

46. Medical History Age at onset Live vaccines? Family history Severity of illness Physical Exam Tonsils? Organomegaly Palpate lymph nodes Chart growth Chest X ray Diagnosis of immune deficiency disorders

47. Phagocyte Cell surface markers Bacteriocidal assay Chemotaxis and opsonization assays NK and Macrophage 51Cr release assays Cytokine release Ig function Isohemagluttinins DT, TT response Anti-pneumococcus Ig levels molecular/DNA studies B cell function CD27 memory cells Nucleic acid enzyme assays molecular/DNA studies T cell function DTH Flow cytometry for subsets PHA/Ag stimulation TCR spectratyping Lab tests

48. Acquired Immunodeficiencies • Secondary immune deficiencies that are the consequences of other diseases • Malnutrition • Chemotherapeutic agents • Deliberate immunosuppression • Untreated autoimmunity • Overwhelming bacterial infection

49. HIV

50. Gp120 binds CD4 Coreceptor binding CCR5 (macrophage tropic) CXCR4 (lymphtropic) Penetration of cell membrane Transcription of RNA to CDNA, remains in latent phase Activated T cells, viral replication and release Macrophages, DC generally serve as reservoirs HIV binding, replication