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Clinical phenotypes and Genetic Mutations in Common Variable
Immunodeficiency
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
Patient 1Patient 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
Laboratory/radiographic dataLaboratory/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
CVID – the basicsCVID – 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
Other immune abnormalitiesOther 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.
CVIDCVID
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)
CVID – a heterogenous diseaseCVID – 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)
Patient 2Patient 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
Laboratory/radiographic dataLaboratory/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
Laboratory/radiographic dataLaboratory/radiographic data
Normal sweat chloride test
Normal ciliary ultrastructure
Immunophenotyping
– ↓ CD19 B lymphocytes 55/MM3 (122-690)
Chest x-ray
– Right lower lobe infiltrate
Laboratory/radiographic dataLaboratory/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
Patient 3Patient 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
Patient 4Patient 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
Family treeFamily tree
?
CVID
Unaffected
?
Research planResearch 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
Research BackgroundResearch 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
Specific AimsSpecific 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
Inclusion/exclusion criteriaInclusion/exclusion criteria
Inclusion
– Individuals meeting the criteria for CVID
Exclusion
– Immunodeficiency of secondary causes
– Individuals with known mutations
Why identify molecular defectsWhy 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
Benefits of molecular diagnosisBenefits 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
OverviewOverview
Cases
Background information on CVID
Review known genetic mutations
Research plan
Draw date Pre 8-7-06 Post 9-7-06 Fold-increase
Pneumovax type 1 0.65 Ug/ml 0.48 Ug/ml <1.0Pneumovax type 3 0.02 Ug/ml 0.02 Ug/ml 1.0Pneumovax type 4 0.04 Ug/ml 0.03 Ug/ml <1.0Pneumovax type 5 0.22 Ug/ml 0.15 Ug/ml <1.0Pneumovax type 6B 0.09 Ug/ml 0.07 Ug/ml <1.0Pneumovax type 7F 0.02 Ug/ml 0.02 Ug/ml 1.0Pneumovax type 8 0.05 Ug/ml 0.03 Ug/ml <1.0Pneumovax type 9N 0.02 Ug/ml 0.01 Ug/ml <1.0Pneumovax type 9V 0.08 Ug/ml 0.05 Ug/ml <1.0Pneumovax type 12 0.03 Ug/ml 0.03 Ug/ml 1.0Pneumovax type 14 6.78 Ug/ml 5.06 Ug/ml <1.0Pneumovax type 18C 0.03 Ug/ml 0.02 Ug/ml <1.0Pneumovax type 19F 0.44 Ug/ml 0.33 Ug/ml <1.0Pneumovax type 23F 0.04 Ug/ml 0.03 Ug/ml <1.0
Impaired ability to produce specific antibodies Impaired ability to produce specific antibodies
IgA Deficiency (IgAD)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
Families with IgAD and CVIDFamilies 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 TH 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
Failure to produce antibodiesFailure 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
ICOS (Inducible costimulatory receptor)ICOS (Inducible costimulatory receptor)
Immunoglobulin-like costimulatory molecule
Member of CD28 family
Expressed on activated T cells
Binds to ICOS-L expressed on APCs.
ICOSICOS
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
ICOSICOS
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%
TACI (TNF receptor family member transmembrane activator and calcium-modulator and cyclophilin ligand interactor)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
TACITACI
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.
TACI – mutation in CVIDTACI – 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.
TACITACI
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.
CD19CD19
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
CD19CD19
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)
BAFF-RBAFF-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.
Patient 1Patient 1
TNFRSF13B sequencing
– Unlikely to be associated with CVID
– Correlagen
– Gene product is TACI
Patient 3Patient 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
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.
Manifestations of CVIDManifestations of CVID
Recurrent upper and lower respiratory tract infections
– Encapsulated and atypical bacteria
Autoimmune disorders (~20%)
Lymphoproliferation/ splenomegaly (1/3)