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Amy Dowden, MD Presentation Transcript

  • 1. Clinical phenotypes and Genetic Mutations in Common Variable Immunodeficiency Amy Dowden, MD University of Iowa Hospitals and Clinics Clinical Immunology Society School in Hypersensitivity and Allergic Diseases August 23, 2008
  • 2. Patient 1
    • 34 year old F
    • PMH
      • Hypothyroidism
      • Vitiligo
      • Pernicious anemia
      • Bronchiectasis
      • Recurrent pneumonias
      • IgA deficiency
    • FH
      • 2 healthy siblings
      • 3 children adopted out, 1 with oophorectomy due to cancer at age 2
    • PE
      • Cachetic, temporal wasting
      • Vitiligo
      • Bilateral rhonchi
  • 3. Laboratory/radiographic data
    • Review from 1996
      • IgA 11 mg/dl (68-378)
      • IgG 965 mg/dl (694-1618)
      • IgM 71 mg/dl (60-263)
      • In vitro studies
        • Decreased response to recall antigens
      • Functional antibody deficiency
      • Sinusitis on CT
    • Lost to follow up
    • Current
      • IgA 19 mg/dl (68-378)
      • IgG 308 mg/dl (694-1618)
      • IgM 45 mg/dl (60-263)
      • Functional antibody deficiency
  • 4. CVID – the basics
    • Diagnosis based on
      • Quantitative immunoglobulin (Ig) levels and function
    • Quantitative IgG < 2 standard deviations below mean
    • May have decreased IgA and IgM
    • Impaired ability to produce specific antibodies on vaccination
    • Exclusion of other causes for antibody deficiency
  • 5. Other immune abnormalities
    • Found in certain subsets of patients
      • Defects in B cell survival/activation
      • Decreased circulating memory B cells
      • T-cell signaling defects
      • Abnormal cytokine secretion
    Castigli E, Geha RS. Molecular basis of Common Variable Immunodeficiency. J Allergy Clin Immunol. 2006 Apr;117(4):740-6.
  • 6. CVID
    • Significance
      • 1 in 25,000 (Europe/N. America)
      • Most common primary immune disorder requiring treatment
      • Significant morbidity/mortality
    • Manifestations
      • Recurrent upper and lower respiratory tract infections
        • Encapsulated and atypical bacteria
      • Autoimmune disorders (~20%)
      • Lymphoproliferation/ splenomegaly (1/3)
  • 7. CVID – a heterogenous disease
    • Most cases sporadic
    • 10% - 15% familial
    • To date 4 known mutations
      • ICOS
      • TACI
      • CD19
      • BAFF-R
    • Misdiagnosis
      • (Bruton’s) X-linked agammaglobulinemia
      • X-linked lymphoproliferative disorder (SH2DIA)
      • X-linked Hyper IgM (CD40L)
  • 8. Patient 2
    • 14 year old F
    • PMH
      • Chronic cough
      • Pneumonia (times 2)
      • Recurrent otitis media
      • Few warts
      • Sertoli-Leydig tumor at age 2
    • FH
      • 2 healthy siblings
      • adopted
    • PE
      • Small cervical LAD
      • Bilateral tympanostomy tubes
      • Few warts on hands
      • Course breath sounds
  • 9. Laboratory/radiographic data
    • Quantitative Immunoglobulins
      • IgA <5 mg/dl (68-378)
      • IgG 535 mg/dl (694-1618)
      • IgM 52 mg/dl (60-263)
    • Normal liver, kidney and thyroid function
    • Sinusitis on sinus CT
  • 10. Laboratory/radiographic data
    • Normal sweat chloride test
    • Normal ciliary ultrastructure
    • Immunophenotyping
      • ↓ CD19 B lymphocytes 55/MM3 (122-690)
    • Chest x-ray
      • Right lower lobe infiltrate
  • 11. Laboratory/radiographic data
    • Functional antibody deficiency
    • In vitro studies
      • Normal fresh and IL-2 enhansed Natural Killer cell activity
      • ↓ Lymphocytic response to alloantigen
      • Slightly ↓ lymphocytic response to IL2
  • 12. Patient 3
    • 12 year old M
    • PMH
      • Upper respiratory tract infections
      • Recurrent otitis media
      • Few warts in the past
    • FH
      • 1 healthy sister
      • 1 sister with CVID
      • adopted
    • PE
      • Bilateral tympanostomy tubes
    • Normal CBC with differential
    • Normal CH50
    • Quantitative Immunoglobulins
      • IgA 52 mg/dl (68-378)
      • IgG 825 mg/dl (694-1618)
      • IgM 48 mg/dl (60-263)
    • Functional antibody deficiency
  • 13. Patient 4
    • 17 year old F
    • PMH
      • Recurrent infections during infancy including pneumonia and otitis
      • Dental caries
      • Few warts in the past
    • FH
      • 1 brother with recurrent infections
      • 1 sister with CVID
      • adopted
    • Normal physical exam
    • Labs
      • Normal quantitative immunoglobulin levels
  • 14. Family tree ? CVID Unaffected ?
  • 15. Research plan
    • Establishment of a clinical phenotype database
    • Identify molecular basis for unknown cases of CVID
      • Known genetic defects account for 10-15% of cases of CVID
      • Focus on familial clusters
      • Similar phenotypes
  • 16. Research Background
    • At UIHC we follow 70+ patients with CVID
      • 4 family clusters
    • In the process of establishing a phenotype database for CVID
      • Demographics, autoimmunity, cancer, gastrointestinal disease, infections, sinus disease, lymphoproliferative disease, family history, treatment, labs
  • 17. Specific Aims
    • Develop distinct clinical phenotypes
    • Determine specific mutations using gene chip analysis from RNA obtained from CVID patients
    • Examine the serum cytokine profile in this population
  • 18. Inclusion/exclusion criteria
    • Inclusion
      • Individuals meeting the criteria for CVID
    • Exclusion
      • Immunodeficiency of secondary causes
      • Individuals with known mutations
  • 19. Why identify molecular defects
    • Provide a definitive diagnosis
    • Establish a diagnosis in atypical presentations
    • Permit prenatal diagnosis/genetic counseling
    • Prognostic/therapeutic implications
      • Genotype-phenotype correlation
      • Early identification of affected presymptomatic individuals
  • 20. Benefits of molecular diagnosis
    • Costs progressively decreasing
    • Short turn around time
    • High reproducibility
    • Patients don’t need to come back
    • Easy to trace individuality
    • DNA is easy to store and hard to destroy
  • 21.  
  • 22.  
  • 23. Overview
    • Cases
    • Background information on CVID
    • Review known genetic mutations
    • Research plan
  • 24. Impaired ability to produce specific antibodies Draw date Pre 8-7-06 Post 9-7-06 Fold-increase Pneumovax type 1 0.65 Ug/ml 0.48 Ug/ml <1.0 Pneumovax type 3 0.02 Ug/ml 0.02 Ug/ml 1.0 Pneumovax type 4 0.04 Ug/ml 0.03 Ug/ml <1.0 Pneumovax type 5 0.22 Ug/ml 0.15 Ug/ml <1.0 Pneumovax type 6B 0.09 Ug/ml 0.07 Ug/ml <1.0 Pneumovax type 7F 0.02 Ug/ml 0.02 Ug/ml 1.0 Pneumovax type 8 0.05 Ug/ml 0.03 Ug/ml <1.0 Pneumovax type 9N 0.02 Ug/ml 0.01 Ug/ml <1.0 Pneumovax type 9V 0.08 Ug/ml 0.05 Ug/ml <1.0 Pneumovax type 12 0.03 Ug/ml 0.03 Ug/ml 1.0 Pneumovax type 14 6.78 Ug/ml 5.06 Ug/ml <1.0 Pneumovax type 18C 0.03 Ug/ml 0.02 Ug/ml <1.0 Pneumovax type 19F 0.44 Ug/ml 0.33 Ug/ml <1.0 Pneumovax type 23F 0.04 Ug/ml 0.03 Ug/ml <1.0
  • 25. IgA Deficiency (IgAD)
    • Most common primary immune deficiency
    • Absent or low levels of IgA (<7 mg/dL)
    • Subset of IgAD patients predisposed to recurrent infections (GI/sinopulmonary)
      • Functional antibody deficiency
    • IgAD may develop into CVID
    • IgAD and CVID may coexist in the same family
  • 26. Families with IgAD and CVID
    • Genetic linkage analysis
      • Susceptibility loci within the MHC locus of chromosome 6
    • MHC class II genes play role in in antigen presentation to T H cells which provide help to B cells for proficient antibody production
    • IgAD and CVID may represent a range in the penetrance of the same disease
    Castigli E, Geha RS. Molecular basis of Common Variable Immunodeficiency. J Allergy Clin Immunol. 2006 Apr;117(4):740-6 . Answers.com
  • 27. Failure to produce antibodies
    • Due to failure of B cells to differentiate into a sufficient number of plasma cells
    • IgAD
      • Some patients have impaired switching to IgA others have a postswitch defect
    • CVID
      • Impaired somatic hypermutation
      • Evidence for a global isotype switching defect
  • 28. ICOS (Inducible costimulatory receptor)
    • Immunoglobulin-like costimulatory molecule
    • Member of CD28 family
    • Expressed on activated T cells
    • Binds to ICOS-L expressed on APCs.
  • 29. ICOS
    • Involved in cytokine secretion
      • Interleukin (IL)-4, IL-5, IL-6, IL-10, tumor necrosis factor (TNF)- α , interferon (IFN)- γ , and granulocyte-macrophage colony-stimulating factor (GM-CSF)
    • Superinduction of IL-10 leads to terminal differentiation of B cells to plasma and memory cells
  • 30. ICOS
    • Grimbacher et al. 2003
    • Individuals with
      • Decreased IgG, M, A
      • Reduced B cells
      • Decreased CD27 + IgM - IgD - switched memory B cells
      • Decrease naïve CD27 - IgM + IgD +
    • Impaired IL-10 and IL-17 secretion
    • Normal phenotype and function of CD4 +
    • All described individuals carry the same homozygous deletion.
    • Incidence 5%
  • 31. TACI (TNF receptor family member transmembrane activator and calcium-modulator and cyclophilin ligand interactor)
    • Two different cohorts
      • CVID
      • IgA deficiency
    • Same mutation within a pedigree in different individuals suggests phenotypes are variants of the same gene defect
  • 32. TACI
    • Expressed on peripheral B cells
      • Preferentially late transitional and marginal zone B cells
    • Interacts with BAFF and April
      • BAFF (B cell activation factor of the TNF family receptor)
      • April is a proliferation-inducing ligand
    • Following ligand binding the intracellular domain binds TRAFS (TNF-associated factors) leading to transcription factor upregulation
    Castigli E, Geha RS. Molecular basis of Common Variable Immunodeficiency. J Allergy Clin Immunol. 2006 Apr;117(4):740-6 .
  • 33. TACI – mutation in CVID
    • Autosomal dominant
    • Autosomal recessive
    • 6 mutations identified to date
      • 3 missense
      • 2 nonsense
      • 1 base insertion
    • 8-10% of patients with CVID
    Castigli E, Geha RS. TACI, isotype switching, CVID and IgAD. Immunol Res. 2007;38(1-3):102-11.
  • 34. TACI
    • No distince B cell phenotype
    • Lymphoproliferative diseases and auto-immune disorders
    Figure adapted from Castigli E, Geha RS. Molecular basis of Common Variable Immunodeficiency. J Allergy Clin Immunol. 2006 Apr;117(4):740-6.
  • 35. CD19
    • Member of the B cell antigen receptor (BCR) complex
    • BCR lowers the threshold for activation after antigen engagement
    • Link between innate and adaptive immune systems
  • 36. CD19
    • Only 4 patients
      • Undetectable (1)
      • Barely detectable
    • Normal B cells in bone marrow and periphery
    • Decreased CD5 + B cells and CD27 + memory B cells
    • Normal B cell development but poor response to antigenic stimuli and inability to mount humoral response
    • No autoimmune features or lympho-proliferation (unlike TACI)
  • 37. BAFF-R
    • Only 1 individual identified
      • Mutation also present in an unaffected relative
    • Limited information at present
    • Individual lacks BAFF-R on B cells
    • Phenotyping reveals a block at the transitional B cell stage
    Castigli E, Geha RS. Molecular basis of Common Variable Immunodeficiency. J Allergy Clin Immunol. 2006 Apr;117(4):740-6.
  • 38. Patient 1
    • TNFRSF13B sequencing
      • Unlikely to be associated with CVID
      • Correlagen
      • Gene product is TACI
  • 39. Draw date Pre 2-25-08 Post 3-24-08 Fold-increase Diphtheria 0.03 U/mL 0.14 U/mL 4.7 Tetanus 0.43 IU/mL 1.13 IU/mL 2.6 Draw date: Pneumovax type 1 0.01 Ug/ml 0.06 Ug/ml NP Pneumovax type 3 0.58 Ug/ml 2.07 Ug/ml 3.6 Pneumovax type 4 0.01 Ug/ml 0.15 Ug/ml NP Pneumovax type 5 0.05 Ug/ml 0.03 Ug/ml NP Pneumovax type 6B 0.02 Ug/ml 0.06 Ug/ml NP Pneumovax type 7F 0.03 Ug/ml 0.11 Ug/ml NP Pneumovax type 8 0.05 Ug/ml 0.59 Ug/ml NP Pneumovax type 9N 0.01 Ug/ml 0.03 Ug/ml NP Pneumovax type 9V 0.03 Ug/ml 0.12 Ug/ml NP Pneumovax type 12F 0.04 Ug/ml 0.05 Ug/ml NP Pneumovax type 14 0.01 Ug/ml 0.02 Ug/ml NP Pneumovax type 18C 0.01 Ug/ml 0.02 Ug/ml NP Pneumovax type 19F 0.07 Ug/ml 0.10 Ug/ml NP Pneumovax type 23 0.01 Ug/ml 0.02 Ug/ml NP
  • 40. Patient 3
    • Quantitative Immunoglobulins
      • IgA 52 mg/dl (68-378)
      • IgG 825 mg/dl (694-1618)
      • IgM 48 mg/dl (60-263)
    • Normal CBC with differential
    • Normal CH50
    • Functional antibody deficiency
  • 41. Chapel H, Lucas M, Lee M, Bjorkander J, Webster D, Grimbacher B, Fieschi C, Thon V, Abedi MR, Hammarstrom L. Common Variable Immunodeficiency Disorders: Division into distinct clinical phenotypes. Blood. 2008 Mar;112:277-86.
  • 42. Manifestations of CVID
    • Recurrent upper and lower respiratory tract infections
      • Encapsulated and atypical bacteria
    • Autoimmune disorders (~20%)
    • Lymphoproliferation/ splenomegaly (1/3)