General Features of Immunodeficiency Diseases

1. General Features of Immunodeficiency Diseases • Disorders affect all major components of immune system • Onset of symptoms early in life • Almost all have recessive inheritance • X-linked diseases are prevalent • Vast majority of unrelated patients have unique mutations • Most common is substitution of one amino acid - missense mutation • Great variability in severity of disease - another factor • Increased incidence of certain types of cancers • Some are accompanied by autoimmune pathology

2. MAJOR CONCEPTS • Main symptom is recurring infections. • Types of infections indicate immune defect. • Family history is important for diagnosis.

4. INCREASED SUSCEPTIBILITY TO INFECTIONSType of recurring infections is clue to defect. 1. Humoral Immunity - encapsulated pyogenic bacteria Antibodies - bacterial pneumonia Complement - disseminated Neisserial infections Phagocytes - systemic uncommon bacterial infections & abscesses 2. Cell-Mediated Immunity - fungi, protozoa & viruses T Cells - opportunistic infections

6. X-linked Bruton’s Agammaglobulinemia • First one recognized and very common • Low or no serum Ig • Decreased or no B cells & plasma cells • Normal T cells & phagocytes • Some patients develop autoimmune disorders

7. Bruton’s tyrosine kinase part of Tec kinase family Although expressed in all hematopoietic cells except T cells & plasma cells, mutation causes selective B cell defect

8. Defective

9. X-linked Hyper-IgM Syndrome • Normal B cell numbers & high serum IgM • IgM specific for T-independent antigens from pathogens • Liver abnormalities & autoantibodies • Impaired antibody responses to T-dependent antigens • Severe bacterial & opportunistic infections • No germinal centers, no memory B cells, few plasma cells, no isotype switching

10. Mutated CD40L • Genetic T cell mutation leading to defective B cell function (phenotype) • Homology to TNF-a • Forms trimer that crosslinks CD40 transducing a signal via TRAF proteins • Mutation in any domain causes disease • Most common are in TNF homology domain

11. Activated TH2 Problem with B cell activation and isotype switching

12. TH1 Also involved in dendritic cell & macrophage activation

13. DiGeorge’s Syndrome *

14. Genetic Basis of Syndrome • Deletion within Chromosome #22 • Smallest deletion involves 24 genes • Candidate gene - transcription factor T-box 1 • Spontaneous deletion in utero accounts for >90% of cases • Associated with fetal exposure to toxins or alcohol

15. Symptoms & Treatments • Cognitive & behavioral problems - neural crest • Abnormal facial features - ears & lips • Abnormal development of parathyroid, heart and thymus • Hypocalcemia & muscle twitching - calcium, vitamin D & parathyroid hormone • Congestive heart failure - heart surgery • Decreased or no T cells - bone marrow transplant with mature T cells • Some patients have autoimmune disorders

16. Defects in Purine Nucleotide Salvage Pathways ADA also converts adenosine to inosine

17. Adenosine Deaminase Deficiency • Most common autosomal SCID • Reduced numbers of T & B cells • Abnormal bone development • Enzyme replacement therapy • Bone marrow transplantation • First human disease to use gene therapy Patients improved in more recent trials

18. Gene Therapy Process called Transduction Retroviral expression vectors are also used

19. PNP also converts guanosine to guanine Rarer - Very similar to ADA Deficiency, but no bone abnormalities Treatments very similar except for gene therapy

20. X-linked SCID • Most common SCID • Decreased numbers of T cells & NK cells • Impaired B cell function, but normal numbers • Bone marrow transplantation • Clinical trials using gene therapy

21. C C g C * WSXWS Signaling defective JAK 3 Shared among IL-2, IL-4, IL-7, IL-9, IL-15 & IL-21 receptors

22. Richmond Times Dispatch March 1, 2003 Panel says FDA should resume some gene trials An advisory committee to the Food and Drug Administration said yesterday that the agency should allow some halted gene therapy trials to resume, but only where there are no alternative treatments. Twenty-seven trials were suspended on Jan. 14 after French researchers reported that a second child in their study of gene therapy had developed leukemia. The children in the French study had a rare immune deficiency syndrome, X-linked severe combined immunodeficiency syndrome, and had few options for treatment. Yesterday, the advisory panel, meeting in Silver Spring, Md., said that the FDA might allow clinical trials of gene therapy in children with the syndrome, called X-Scid, if no other treatment were available. Note: FDA allowed clinical trials to resume at end of 2004 About 6 patients have developed leukemia or T cell tumors

23. Chronic Granulomatous Disease • X-linked & autosomal forms • Uncontrolled bacterial & fungal infections • Pneumonia & abscesses • Chronic inflammation & macrophage activation leading to granulomas • Granulomas can obstruct digestive & urogenital tracts

24. superoxide dismutase Defect in superoxide production & subsequent products

25. Cytochrome b558 = + A X A A p67+p40+Rac = Trimer

26. Chronic Granulomatous Disease • Bone marrow transplantation for all forms • X-linked most common form of CGD • Interferon-g: Experimental treatment for X-linked form results in 10% normal superoxide level & resistance to infections greatly improved • Clinical trials for gene therapy for X-linked form - variable results Monosomy 7 in one trial

27. Chediak-Higashi Syndrome • Autosomal progressive disorder: multi-systems • Mutated CHS1 gene also called LYST • Encodes transport protein • Problem with vesicular transport • Defective fusion of granules & lysosomes • Material is not degraded & accumulates • Large granular inclusions form & accumulate • Causes cell death

28. Granular Inclusion

29. Symptoms & Treatment • Partial albinism - abnormal melanocytes • Bleeding disorders - abnormal platelets • Central nervous system deterioration - gradual • Jaundice - liver abnormalities • Extra & intracellular bacterial infections especially respiratory & skin • Decreased killing by NK cells, PMN and macrophages • Lymphoreticular cancers <- EBV • Bone marrow transplant - CNS problems remain

30. Antimicrobial Agents Gamma Globulin Bone Marrow Transplant Enzyme Replacement Interferon-g Gene Therapy All Diseases Hypogammaglobulinemia SCID, T cell defects, CGD & CHS ADA & PNP X-linked CGD ADA, X-linked SCID & X-linked CGD Treatments Diseases