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Primary Immunodeficiencies

Primary Immunodeficiencies. Dr. Katia Sitnitskaya. Host defense. Innate immunity Complement: alternative pathway Phagocytes: - neutrophils - macrophages Natural killers. AG-specific immunity Complement: classical pathway AG + AB T cell response

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Primary Immunodeficiencies

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  1. Primary Immunodeficiencies Dr. Katia Sitnitskaya

  2. Host defense Innate immunity • Complement: alternative pathway • Phagocytes: - neutrophils - macrophages • Natural killers AG-specific immunity • Complement: classical pathway AG + AB • T cell response • B cell: AB production

  3. US: how many we are talking about ?

  4. Most common ?

  5. Complement cascade youDON’T HAVE TOremember

  6. Complement:- opsonization: C3b, C5b - chemotaxis: C3a, C5a - membrane attack: C5-9 Opsonization Chemotaxis

  7. Complement deficiencies: very rare (-) opsonins + chemotaxis Pyogenic infections

  8. Complement deficiency • C5-9 “terminal pathway” deficiency: 40% relapse of Meningoccal infection • 3 – 5% of cases of Meningococcal infection = complement deficiency • AB-sensitized sheep RBC: measurement of total hemolytic c. by classical pathway (CH50) • Unsensitized rabbit RBC; measurement of total hemolytic c. by alternative pathway (AH50)

  9. Phagocytic disorders

  10. Phagocytic disorders LAD “Indigestion” = CGD, Chediak-Higashi

  11. Phagocytic Disorders: 1. “commuting” • LAD: • - the defect is a lack of a neutrophil adhesion molecule = no emigration into tissues. • presents with delayed separation of the umbilical cord, recurrent SBIs, leukemoid • reactions

  12. Leukocyte adhesion deficiency (LAD) A. Normal neutrophils aggregate B. Neutrophils from a patient with LAD type 1 fail to aggregate in vitro C. Patients with LAD type 1 have periodontitis & recurrent GI, GU, and respiratoryinfections

  13. Congenital agranulocytosis Kostmann Disease • AR, 1: 1 000 000 • An abnormal G-CSF–induced intracellular signal transduction ? • ANC < 500/mm3 + normal WBC count because of the monocytosis. • Abnormal CD64+ (FCgRI receptor) on neutrophils • Mild anemia may be present from chronic inflammation. • + Hyper-g-globulinemia. • Mortality rate without Tx: 70% within the 1-st year of life • Tx: failure of G-CSF BMT, or stem cell transplantation.

  14. Phagocytic disorders 1. NADPH oxidase catalyzesreduction of O2 to superoxide anion (O–•2 ) 2. Superoxide dismutase convert it to H2O2 3. Neutrophil-derived myeloperoxidase (MPO) converts H2O2 into a HOCl–bleach Cl2

  15. Clinical Features of CGD • A. Inflammation of the nares. • Large granuloma in the neck • Severe gingivitis • An esophageal stricture caused • by a granuloma. • Resolution after treatment with CSs

  16. Chediak-Higashi syndrome • AR, the long arm of chromosome 1 • The lysosomes fail to fuse with the phagosome. • Neutropenia + diminished chemotaxis + giant lysosomes • Dx: chemotaxis assay • Decreased NK functions. • The platelets are abnormal (easy bruising). • Oculocutaneous albinism, photophobia, enterocolitis and peripheral neuropathy. • BMT has been used with excellent results in several cases. • 85% of children with CHS, develop lymphoma-like condition which generally conduces to death. • Prenatal Dx: giant neutrophil granules in the fetal blood.

  17. Myeloperoxidase deficiency • Common 1 : 2000, AR • Dercreased intracellular killing (no bleach) • Absence of myeloperoxidase enzyme in neutrophil and monocyte granules. • MPO deficiency + diabetes mellitus = Candidal sepsis + osteo • Most patients are asymptomatic • Dx: chemoluminescence test • Vacuolized neutrophils

  18. Phagocytic disoders A. Normal peripheral blood smear • Peripheral blood smear from a patient with the Chédiak–Higashi syndrome: • large perinuclear granules. • C. Peripheral-blood smear from a patient with agranulocytosis: the cytoplasm is pale, no granules are present, and nuclei are notched and hyposegmented. • D. Nitroblue tetrazolium test (NBT) in normal neutrophils: phagocytosis results in dark-blue staining of the cytoplasm • NBT in neutrophils from a patient with CGD: there is no phagocytosis = no dark-blue • cytoplasmic staining. • F. A hair from a patient with the Chédiak–Higashi syndrome in which giant granules are present, ( normal hair on thr right).

  19. Phgocytic disorders summary Common infections with GN and catalase (+), like Staph. aureus, Pseudomonas a. + Aspergillus.

  20. “Central” immunodeficiencies: bone marrow / thymic events 1. Bruton’s A-g-globulinemia: XR, chrom. Xq22 2. DiGeorge Syndrome = Thy. aplasia: microdelition, chrom. 22q 3. Severe Combined ImmunoDeficiency (SCID): multi-modal 1 3 2

  21. T cell disorders

  22. Severe combined ImmunoDeficiency (SCID)

  23. SCID Loss of the MHC molecule = “Bare lymphocyte syndrome”: no recognition of other cells

  24. SCID • The only host defenses are: • Complement • Phagocytosis • Maintenance: • Bactrim Px, Azithro Px • IVIG • Salvage: • Recombinant ADA injections • BMT

  25. DiGeorge Syndrome: “CATCH-22” Cardiac malf. Abnormal face Thymic hypopl. Cleft palate Hypo-Ca-emia • Sporadic microdeletion of 22q • Hypertelorism, down-slanted eyes, + cleft palate (“midline defects”) Developmental defect of the 3-d & 4-th pharyngeal pouches • No thymus = low T cell counts • No parathyroid glands = hypo-Ca-emic seizures • CV: interrupted aortic arch & truncus arteriosus • Treatment: thymus transplant

  26. Ataxia-Telangiectasia • AR, chromosome 11 • 1 case in 100,000 births • Single gene mutation results in impaired repair of DNA damage = cancer in1/4 ( lymphoma) • Usually presents in the 2-d year of life as a lack of balance and slurred speech. • Ocular telactasia before age of 6. Mild MR in 1/3 • Progressive cerebellar degeneration (CT: atrophy) + immunodeficiency in 2/3 + radiosensitivity (x-ray) • AFP, may be small thymus, dys-g-globulinemia ( Ig G2,4 & A)

  27. Wiscott-Aldrich disease • WASP gene on Xp11 chromosome = X-linked recessive • Defective cytoskeleton of T cells and platelets • TCP + Eczema + recurrent sino-pulmonary infections, HSV / CMV, PCP • Labs: small Plt, T cells, B cells, Ig A & E, specific ABs • Tx:IVIG BMT • Pre-natal Dx: EM of fetal lymphocyte

  28. IL-12 receptor deficiency Monocytes and macrophages bind IFN- g activation: 1. production of hydrogen peroxide (H2O2) 2. synthesis & release ofIL-12 & tumor necrosis factor (TNF) A. Resolving mycobacterial infection with normal granuloma formation B. An AR mutation of the IFN-g receptor : mycobacteria survive in macrophages C. Same patient: no granuloma IL-12 produced by macrophages and dendritic cells in the presence of a pathogen, binds to its receptors on T cells and NK cells inducing the release of IFN-g

  29. T cell deficiencies: summary

  30. B cell disorders

  31. Bruton’s X-linked A-g-globulinemia • Absence or deficiency of a Bruton’s tyrosine kinase: maturation arrest of pre-B cells • Levels of all Ig levels are less than 10% of normal. • Infections start after 5 months of age: capsulated ( H. influenzae, Strep. pneumoniae, Giardia lamblia, ECHO viruses) . Tiny tonsils, • Molecular confirmation of the Dx: fluocytometry • Treatment: IVIG

  32. Selective Ig A deficiency • Most common immunodeficiency: 1: 700 in US • Some cases are AR. • 1 : 300 in atopic population • Majority of patients are clinically normal • Ig A < 5: recurrent / chronic sinopulmonary, GI, GU infections • Allergy, GI (celiac disease, UC), JRA, SLE • IgG is c/indicated unless IgG deficiency also present

  33. Hyper-E syndrome • Pruritic dermatitis (eczema) • Recurrent staphylococcal abscesses of skin, lung, joints, etc. • Eosinophilia of blood and sputum • Ig G, M, A usually normal • Extremely high Ig E > 1000 , high Ig D • Diminished response to immunization • Poor cellular and humoral response to neoantigens • Tx: IVIG BMT

  34. T helper Hyper-M X-linked disorder Patients have abnormal CD4 ligand on T cells, and can not properly signal B cells Thus, this is really a T cell problem; the B cells work fine Block in switching from Ig M to IgG, IgA, IgE B cell

  35. Hyper-M X-linked disorder • X-linked recessive: Xq26 • + sporadic cases • Recurrent pyogenic, mostly • sinopulmonary, infections • Sclerosing cholangitis • Increased incidence of autoimmune • and lymphoproliferative disorders • Low Ig G & Ig • Neutropenia, TCP, anemia • Tx: IVIG

  36. Common Variable Immune Deficiency (CVID) • AD / X-linked • Onset after 10 y., recurrent sinopulmonary infections & other pyogenic • Lymphadenopathy and splenomegaly may be present • IL-2, IFN-g, CD40L (defective CD4 function ) • IgG < 50% (< 250), Ig A & M • No specific Ab production / no response to vaccines • Anti - B cell autoantibodies • Patients may have a higher occurrence of atopic / rheumatalogic • diseases, lymphoid hyperplasia • Treatment: IVIG to keep IgG > 400

  37. Transient hypo-g infantorum • Delayed onset of IgG synthesis, but always > 200 • Physiological nadir of IgG level 430 – 660 @ 4 – 12 mo. Of age • Onset of symptoms coincides with decline in matrnal IgG level • Normal levels of Ig A & M • Normal IgG response to immunization • Mature B cells & plasma cells are present • Resolves by 24 – 36 months of age

  38. B cell disorders summary

  39. Warning Signs of Primary Immunodeficiency Disorders

  40. D. Dube et al, POSTGRAD MED, 2002

  41. Workup for suspected P.I.D.

  42. IVIG is indicated for: - Bruton’s a-g-globulinemia - Hyper-M & Hyper-E - CVID & Ig subcl. = if NO SPECIFIC Abs ! - SCID & Wiscott-Aldrich

  43. Indications for BMT: • Hyper-E syndrome • SCID • Wiscott-Aldrich • Chediak-Higashi • Kostmann Disease

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