Farmacia-Bioquimica 2007

1. Immunodeficiency Farmacia-Bioquimica 2007

2. What is Immunodeficiency? • A failing of one or more of the body’s defensive mechanisms resulting in morbidity or mortality. • Any part of the immune system can be deficient – cells, proteins, signalling mechanisms……. • The body is susceptible to infection by organisms that meet with little or no resistance. • Or, in certain cases, other homeostatic systems in the body will be disrupted by the defect. • Severity is variable. • Immunodeficiency may be Primary or Secondary.

3. Primary Immunodeficiency: • Arises without a pre-existing causative disorder. • Usually has a genetic basis.

5. Secondary Immunodeficiency: • Arises because of another pre-existing pathology or intervention, e.g. • Infection (Ex.: HIV) • Renal failure, or protein losing enteropathy • Leukaemia or Lymphoma • Myeloma • Extremes of age • Certain Drug Therapies • Undernourishment

6. Definition A group of inherited disorders, characterized by recurrent and/or unusual infections in different organs of the body. 1. Antibody deficiencies 2. Cellular deficiencies 3. Phagocytic disorders 4. Complement deficiencies 5. Combined deficiencies

11. OS DEZ SINAIS DE ALERTA PARA IMUNODEFICÊNCIA PRIMÁRIA NA CRIANÇA • Duas ou mais pneumonias no último ano • Quatro ou mais novas otites ou sinusites no último ano • Estomatites de repetição ou monilíase > 2 meses • Abscessos de repetição ou ectima • Uma infecção sistêmica grave (meningite, osteoart, sepse) • Infestações intestinais de repetição / Diarréia crônica • Asma grave, Colagenoses, Doenças autoimunes • Efeito adverso grave ao BCG e/ou infecção por M. atípica • Fenótipo sindrômico associado à imunodeficiência • História familiar de imunodeficiência

14. Diagnosing Primary Immunodeficiency What are primary immunodeficiencies? Antibody deficiency T cell defects SCID Cytokine defects Neutrophil defects Complement Hereditary angio oedema How are they diagnosed? Immunochemistry Cellular assays

27. Characteristics of infections • Increasing susceptibility to infections • Increasing severity of infection • Increasing duration of infections • Unusual infection • Infection with opportunistic agents • Continuous illness • Dependence to antibiotics

28. Manifestações clínicas iniciais de ID primária em 92 crianças(Sta Casa -SP, UNIFESP-EPM) Alergia respiratória Doenças do colágeno e auto-imune Fenótipo ID 9.8% 9.8% 7.6% Suscetibilidade aumentada às infecções 74.3%

32. Antibody deficiencies include: • Common variable immunodeficiency (CVID) • X-linked agammaglobulinemia (XLA) • Selective IgA deficiency (SIgAd) • Selective IgG subclass deficiency (SIgGsd) • Hyper IgM syndrome (HIgM) • Transient hypogammaglobulinemia of Infancy (THI) • Functional antibody deficiency

33. IgA Deficiency • 1:500 (IgA  5 mg/dL) • Respiratory or gut infection • Worse if IgG subclass deficiency • Coeliac disease • Major reactions to blood product: Ab a-IgA • Foregut (the anterior part of the embryonic alimentary canal of a vertebrate) lymphoma and carcinoma

34. IgG Subclass and IgA DeficienciesPatterns of Illness • Chronic/recurrent upper respiratory infections, especially sinusitis • Tendency to develop respiratory and gastrointestinal allergies and autoimmunity

35. IgG Subclass – IgA-D – CVIDPolar Ends of a Common Disease? • IgA deficiency frequently coexists with IgG subclass deficiency, especially IgG2 and IgG4 • Linkage to Class III region of HLA • 50% incidence of IgA-D in children of patients with CVID • Occasionally IgA deficient patients have been noted to progress to CVID

36. Common Variable Immunodeficiency • Panhypogammaglobulinemia, usually with lymphadenopathy and splenomegaly • Absence of clear abnormalities in T and B cell subsets • Chronic/recurrent respiratory infections, & diarrhea, especially due to Giardia • Tendency to develop autoimmunity and lymphoid malignancies • Linkage to HLA Class III Region in 2/3 of patients • One gene identified: ICOS (B7h) (activation antigen on T cells)

37. Common Variable Immunodeficiency • IgG deficiency is core feature • Lifelong illness • Family history of Ab deficiency in 20% • Probably a number of mechanisms • Recurrent sinopulmonary infections • Granulomatous disease • Autoimmunity & cytopenias

38. Pure T cell defects * Di George Syndrome • Branchial arch defects • hypoparathyroidism • aortic arch/truncus defects • thymic aplasia • dysmorphic • Translocation chromosome 22 • Variable presentation

39. Severe Combined Immunodeficiency • “T-B+” • cytokine g chain defect X linked • Jak 3 deficiency AR • “T-B-” • recombinase deficiency AR • ADA Deficiency = (Adenosine Deaminase) AR

40. Common Features of Severe Combined Immunodeficiency (SCID) • Failure to thrive • Onset of infections in the neonatal period • Opportunistic infections • Chronic or recurrent thrush • Chronic rashes • Chronic or recurrent diarrhea • Paucity of lymphoid tissue

41. Severe Combined Immunodeficiency Common Laboratory Features • Hypogammaglobulinemia • Absence of antibody responses to immunizations • Absent mitogen responses • Low or absent T cells • Often low or absent B cells

42. Severe Combined Immunodeficiency Syndromes (SCID) • X-linked SCID (c deficiency) • Jak3 kinase deficiency • Adenosine deaminase deficiency • Purine nucleoside phosphorylase deficiency • Bare lymphocyte syndrome • RAG1 and RAG2 deficiency

43. X-Linked SCID: Common Cytokine Receptor Gamma Chain (gc) Deficiency • Most common form of SCID (40%) • Very low T cells and NK cells with low to normal numbers of B cells • Responsible gene: c – the common subunit of receptors for IL-2, IL-4, IL-7, IL-9, and IL-15

45. Severe Combined Immunodeficiency Treatment • Bone marrow transplantation, preferably from a histocompatible sibling • Gene therapy

46. Phagocyte Deficiencies: • Chronic granulomatous disease (CGD) • Leukocyte adhesion deficiency (LAD I) • Chediak-Higashi syndrome • IL-12/IFN pathway deficiencies • Chronic or cyclic neutropenia

48. Leukocyte Adhesion Deficiency I • Severe tissue infections due to absence of adhesion molecules (b-integrins CD11/CD18) on leukocytes • Inability to make pus due to entrapment of phagocytes within the vasculature • Lethal within the first decade of life without bone marrow transplant

49. Omphalitis in LAD I patient

50. Chronic Granulomatous Disease • Inability of phagocytes to generate hydrogen peroxide due to mutations in one of four proteins comprising the NADPH oxidase • Severe tissue infections with catalase positive organisms, esp. Staph aureus, Serratia marcescens, mycobacteria, and fungi such as Aspergillus