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Humoral Immunodeficiencies
Shobhita KatiyarJULY 20, 2016
PID : distribution
Distribution of identified PIDs in ESID registry database
B cell development
Surface receptors on developing B cell
CD 19, CD21 and CD 81
Clinical cytometry society,2008
B cell development
J Clin Immunol 2015
B cell immunodeficiency: Warning signs
Question: Which is the most common antibody produced in the body?• IgG• IgM• IgA• IgE• IgD
Question: Which is the most common antibody in circulation in the body?• IgG• IgM• IgA• IgE• IgD
Agammaglobulinemias
Agammaglobulinemias
X Linked Agammaglobulinemia (XLA)
First recognized human immune deficiency Discovered in 1952 by Colonel Ogden Bruton Case report : 8-year-old boy, recurrent infections over a 4-year period
- Majority of infections: pneumococcus - Bruton attempted to vaccinate → no γ globulin was production - Treated with monthly intramuscular injections of human γ globulin with significant clinical improvement - No family history
Subsequent cases revealed a similar clinical phenotype with an X-linked pedigree
Agammaglobulinemia.Pediatrics,1952, Clin Exp Immunol,2000.
Introduction
Epidemiology
IncidenceUnknown because general population screening for the disorder is not done (1/3 new mutation)
Prevalence1/10,000 in the general population
Variable (1/379,000 in USA, 1/100,000 in Norway)
Clinical and Molecular Allergy ,2008
Pathophysiology Cause : mutations in the human BTK gene – halts B cell development
In 1993, two groups of investigators independently/simultaneously discovered mutated gene in XLA.
European group called atk gene→ ammaglobulinemia tyrosine kinase
American group called bpk gene → B-cell pro-genitor kinase
A compromise was reached with the term;
‘Btk (Bruton's tyrosine kinase)’ in honor of Dr. Bruton
Immunological Reviews 2005Cell 1993
Btk in B cell signaling
Btk gene & protein
Contains 19 exons → 37 kb of DNA Intracellular signal transduction molecule
- Member of Tec family ; 75 kDa cytoplasmic tyrosine kinase
National Library of Medicine,2012
BTK protein consists of 5 functional domains
- Pleckstrin Homology (PH) domain
- Tec homology (TH) domain
- Src homology 3 (SH3) domain
- Src homology 2 (SH2) domain
- Catalytic kinase (SH1) domain
Mutations in all domains of the BTK gene have been shown to cause XLA.
protein-protein interactions
Catalytic activity
Journal of Hematology and Oncology, 2013
Question: Which cell population will you gate for analyzing Btk expression in a suspected patient?
Btk expression in hematopoietic cells
Btk Mutation
>600 different mutations in the BTK gene have been found
90% : Single base pair substitution & insertion or deletion < 5 bp
No clear correlation has been found between mutation location and
clinical phenotype. 55% of males have no family history of XLA - De novo causing mutation : 15%-20% - Mother is a carrier of a disease-causing mutation : 80%-85% Female carriers of XLA can be identified by the presence of either; - non-random X chromosome inactivation in their B cells or - mutated gene (if known in the family)
National Library of Medicine,2012.
Clinical Manifestations
The Indian Journal of Pediatrics,2016
Diagnosis Family history Clinical manifestations Intermittent neutropenia can occur at the onset of an acute infection Low serum IgG, IgM and IgA level Peripheral blood CD19 B-cell counts < 2%
Laboratory investigation by Prenatal diagnosis: detection of the mutated gene in chorionic villus
or amniocentesis samples Confirmation by demonstrating; - absence of BTK protein in monocytes (flowcytometry) - detection of a mutation in BTK in DNA (sequence analysis)
Flowcytometry
Btk expression in monocytes
Treatment Early diagnosis and treatment would improve the survival Intravenous immunoglobulin (IVIG) and antibiotic prophylaxis are
conventional treatments → increased survival rate
Genetic counselling, carrier detection, and prenatal diagnosis
Gene therapy
Blood, 2004
Common variable immunodeficiency
CVID Term coined in 1971 by WHO committee to separate less well
defined antibody deficiency syndrome from others
Causes of CVID: largely obscure; no universally accepted definition
• A group of antibody deficiencies that lack a more specific genetic or phenotypic classification
• Patients with antibody deficiency (no secondary causes for it) lacking uniform genetic defect and clinical features
Epidemiology Prevalence 1 in 25,000 to 1 in 50,000
Most patients are diagnosed between the ages of 20 and 40 years, approximately 20% are under the age of 20
Affects both sexes equally, boys > girls in children
Blood,2012
CVID: Diagnostic Criteria
Genetics 90% sporadic cases – unknown defect 10% Familial - AD with variable penetrance(80%) - AR (20%)
CVID: genetic defects
Arthritis Research & Therapy 2012
British journal of Hematology,2009
Clinical manifestations
Blood,2008
Autoimmunity in CVID Others include Neutropenia Pernicious anaemia Anticardiolipin Ab Antiphospholipid syndrome Diabetes mellitus Juvenile Idiopathic Arthritis Uveitis Multiple sclerosis Systemic lupus erythematosus Autoimmune thyroid disease Lichen planus Vasculitis Vililago
American Society of Hematology,2012
• Q: An 8 year old boy p/w lower limb predominant arthritis of 4 m duration. It was not controlled with NSAIDs alone and was started on SSZ f/b Mtx in combination for it.
• Again, there was incomplete response and he also developed bloody diarrhoea 2 months later. He was investigated for possible PID with autoimmunity. No family history.
• Hb = 8gm%, TLC = 14000, N90 L6, Plt = 3.3 Lac• STP = 5.6 gm, Alb. = 3.2 gm, IgG, A and M
• Imp: Panhypogamamglobulinemia• Diagnosis & next step?
Treatment Primary treatment is antibody replacement: IVIG or SCIG
IVIG: 400 – 600 mg/Kg q3-4 weeks
SCIG: 100 – 150 mg/Kg/week
Ch. Lung Disease and IBD: Higher doses
Trough levels: 7gm/L
Infection prevention: Antibiotic prophylaxis
Autoimmune phenomena: Steroids, IS, Rtx
Severe hematological changes (chronic transfusion need, leukopenia,
Thrombocytopenia) & secondary malignancies - Stem cell transplantation
Selective IgA deficiency
Introduction IgA: first described in serum in 1953; Selective IgA deficiency: first reported in
1964
Incidence – Caucacians > Asians
No well defined genetic susceptibility → AD, AR and sporadic
Most abundant Ab isotype produced in body
Subclasses: IgA 1 and IgA 2 → locus α1 and α2 on chromosome 14
Circulating IgA : monomeric
- predominantly IgA 1
- Produced in BM from plasma cell
Secretory IgA : dimeric
- predominantly IgA 2
- Produced locally in the mucosal tissue
Definition
Selective IgA Deficiency Male / Female > 4 yrs. of age
Serum IgA < 7 mg/dL
Normal serum IgG and IgM
Other causes of hypogammaglobulinemia have been excluded
Normal IgG antibody response response to vaccination
Partial IgA Deficiency Serum IgA > 7 mg/dL but 2 SD below for normal of that age
Ig A Most abundant Ab isotype produced in body
Subclasses: IgA 1 and IgA 2 → locus α1 and α2 on chromosome 14
Exists in monomeric and dimeric forms
Circulating IgA : monomeric
- predominantly IgA 1
- Produced in BM from plasma cell
Secretory IgA : dimeric
- predominantly IgA 2
- Produced locally in the mucosal tissue
Pathogenesis Primary defect: block in differentiation of B cells → IgA secreting
plasma cell (? At the level of stem cells)
α heavy chain deletions: chromosome 14
Abnormalities in cytokine network: IL-4,6,7,10,21 and TGF-β
Mutations reported : TACI, APRIL,TNFRSF13B
Disease association with MHC haplotype 8.1(HLA A1,B8,DR3 and DQ2) → ↑ risk of developing disease
Lancet, 1985
Clinical Manifestations Wide spectrum of manifestations:
Most patients asymptomatic → 90-95%
Symptomatic patients: Mucosal infections (RS & GI) Reccurrent sinopulmonary infections
Haemophilus influenzaeStreptococcus pneumoniae
Gastrointestinal infections/disordersGiardia lambliaMalabsorptionCeliac diseaseUlcerative colitisNodular lymphoid hyperplasia
Allergic disorder
Autoimmune conditions (Commonest after infections)Idiopathic thrombocytopenic purpuraHemolytic anemiaJuvenile rheumatoid arthritisThyroiditisSystemic lupus erthematosus
Malignancies
Clinical Manifestations
Treatment
Asymptomatic patients: none
Mainstay treatment : treatment of associated diseases
IgG subclass deficiency/antibody deficiency → IVIG,SCIG with
product containing minimal IgA
Prevent anaphylactic reaction secondary to blood transfusion
Recurrent respiratory infections : antibiotics
Observation: Patients may progress to develop CVID.
Take Home Message
• Humoral immunodeficiencies : commonest PIDsExclude 2o causes of Ab deficiency
• Clinical features:Symptomatic after 1 year of ageEncapsulated bacterial infections (Resp. & GI)
• Improving prognosis:Suspect PID!!Timely treatment and prophylaxis of infections