humoral immunodeficiencies
TRANSCRIPT
![Page 1: Humoral Immunodeficiencies](https://reader035.vdocument.in/reader035/viewer/2022062503/589df9161a28ab1e718b5705/html5/thumbnails/1.jpg)
Humoral Immunodeficiencies
Shobhita KatiyarJULY 20, 2016
![Page 2: Humoral Immunodeficiencies](https://reader035.vdocument.in/reader035/viewer/2022062503/589df9161a28ab1e718b5705/html5/thumbnails/2.jpg)
PID : distribution
Distribution of identified PIDs in ESID registry database
![Page 3: Humoral Immunodeficiencies](https://reader035.vdocument.in/reader035/viewer/2022062503/589df9161a28ab1e718b5705/html5/thumbnails/3.jpg)
B cell development
![Page 4: Humoral Immunodeficiencies](https://reader035.vdocument.in/reader035/viewer/2022062503/589df9161a28ab1e718b5705/html5/thumbnails/4.jpg)
Surface receptors on developing B cell
![Page 5: Humoral Immunodeficiencies](https://reader035.vdocument.in/reader035/viewer/2022062503/589df9161a28ab1e718b5705/html5/thumbnails/5.jpg)
CD 19, CD21 and CD 81
![Page 6: Humoral Immunodeficiencies](https://reader035.vdocument.in/reader035/viewer/2022062503/589df9161a28ab1e718b5705/html5/thumbnails/6.jpg)
Clinical cytometry society,2008
B cell development
![Page 7: Humoral Immunodeficiencies](https://reader035.vdocument.in/reader035/viewer/2022062503/589df9161a28ab1e718b5705/html5/thumbnails/7.jpg)
J Clin Immunol 2015
![Page 8: Humoral Immunodeficiencies](https://reader035.vdocument.in/reader035/viewer/2022062503/589df9161a28ab1e718b5705/html5/thumbnails/8.jpg)
B cell immunodeficiency: Warning signs
![Page 9: Humoral Immunodeficiencies](https://reader035.vdocument.in/reader035/viewer/2022062503/589df9161a28ab1e718b5705/html5/thumbnails/9.jpg)
Question: Which is the most common antibody produced in the body?• IgG• IgM• IgA• IgE• IgD
![Page 10: Humoral Immunodeficiencies](https://reader035.vdocument.in/reader035/viewer/2022062503/589df9161a28ab1e718b5705/html5/thumbnails/10.jpg)
Question: Which is the most common antibody in circulation in the body?• IgG• IgM• IgA• IgE• IgD
![Page 11: Humoral Immunodeficiencies](https://reader035.vdocument.in/reader035/viewer/2022062503/589df9161a28ab1e718b5705/html5/thumbnails/11.jpg)
Agammaglobulinemias
![Page 12: Humoral Immunodeficiencies](https://reader035.vdocument.in/reader035/viewer/2022062503/589df9161a28ab1e718b5705/html5/thumbnails/12.jpg)
Agammaglobulinemias
![Page 13: Humoral Immunodeficiencies](https://reader035.vdocument.in/reader035/viewer/2022062503/589df9161a28ab1e718b5705/html5/thumbnails/13.jpg)
X Linked Agammaglobulinemia (XLA)
![Page 14: Humoral Immunodeficiencies](https://reader035.vdocument.in/reader035/viewer/2022062503/589df9161a28ab1e718b5705/html5/thumbnails/14.jpg)
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
![Page 15: Humoral Immunodeficiencies](https://reader035.vdocument.in/reader035/viewer/2022062503/589df9161a28ab1e718b5705/html5/thumbnails/15.jpg)
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
![Page 16: Humoral Immunodeficiencies](https://reader035.vdocument.in/reader035/viewer/2022062503/589df9161a28ab1e718b5705/html5/thumbnails/16.jpg)
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
![Page 17: Humoral Immunodeficiencies](https://reader035.vdocument.in/reader035/viewer/2022062503/589df9161a28ab1e718b5705/html5/thumbnails/17.jpg)
Btk in B cell signaling
![Page 18: Humoral Immunodeficiencies](https://reader035.vdocument.in/reader035/viewer/2022062503/589df9161a28ab1e718b5705/html5/thumbnails/18.jpg)
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
![Page 19: Humoral Immunodeficiencies](https://reader035.vdocument.in/reader035/viewer/2022062503/589df9161a28ab1e718b5705/html5/thumbnails/19.jpg)
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
![Page 20: Humoral Immunodeficiencies](https://reader035.vdocument.in/reader035/viewer/2022062503/589df9161a28ab1e718b5705/html5/thumbnails/20.jpg)
Question: Which cell population will you gate for analyzing Btk expression in a suspected patient?
![Page 21: Humoral Immunodeficiencies](https://reader035.vdocument.in/reader035/viewer/2022062503/589df9161a28ab1e718b5705/html5/thumbnails/21.jpg)
Btk expression in hematopoietic cells
![Page 22: Humoral Immunodeficiencies](https://reader035.vdocument.in/reader035/viewer/2022062503/589df9161a28ab1e718b5705/html5/thumbnails/22.jpg)
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.
![Page 23: Humoral Immunodeficiencies](https://reader035.vdocument.in/reader035/viewer/2022062503/589df9161a28ab1e718b5705/html5/thumbnails/23.jpg)
Clinical Manifestations
The Indian Journal of Pediatrics,2016
![Page 24: Humoral Immunodeficiencies](https://reader035.vdocument.in/reader035/viewer/2022062503/589df9161a28ab1e718b5705/html5/thumbnails/24.jpg)
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)
![Page 25: Humoral Immunodeficiencies](https://reader035.vdocument.in/reader035/viewer/2022062503/589df9161a28ab1e718b5705/html5/thumbnails/25.jpg)
Flowcytometry
Btk expression in monocytes
![Page 26: Humoral Immunodeficiencies](https://reader035.vdocument.in/reader035/viewer/2022062503/589df9161a28ab1e718b5705/html5/thumbnails/26.jpg)
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
![Page 27: Humoral Immunodeficiencies](https://reader035.vdocument.in/reader035/viewer/2022062503/589df9161a28ab1e718b5705/html5/thumbnails/27.jpg)
Blood, 2004
![Page 28: Humoral Immunodeficiencies](https://reader035.vdocument.in/reader035/viewer/2022062503/589df9161a28ab1e718b5705/html5/thumbnails/28.jpg)
Common variable immunodeficiency
![Page 29: Humoral Immunodeficiencies](https://reader035.vdocument.in/reader035/viewer/2022062503/589df9161a28ab1e718b5705/html5/thumbnails/29.jpg)
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
![Page 30: Humoral Immunodeficiencies](https://reader035.vdocument.in/reader035/viewer/2022062503/589df9161a28ab1e718b5705/html5/thumbnails/30.jpg)
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
![Page 31: Humoral Immunodeficiencies](https://reader035.vdocument.in/reader035/viewer/2022062503/589df9161a28ab1e718b5705/html5/thumbnails/31.jpg)
CVID: Diagnostic Criteria
![Page 32: Humoral Immunodeficiencies](https://reader035.vdocument.in/reader035/viewer/2022062503/589df9161a28ab1e718b5705/html5/thumbnails/32.jpg)
![Page 33: Humoral Immunodeficiencies](https://reader035.vdocument.in/reader035/viewer/2022062503/589df9161a28ab1e718b5705/html5/thumbnails/33.jpg)
![Page 34: Humoral Immunodeficiencies](https://reader035.vdocument.in/reader035/viewer/2022062503/589df9161a28ab1e718b5705/html5/thumbnails/34.jpg)
![Page 35: Humoral Immunodeficiencies](https://reader035.vdocument.in/reader035/viewer/2022062503/589df9161a28ab1e718b5705/html5/thumbnails/35.jpg)
Genetics 90% sporadic cases – unknown defect 10% Familial - AD with variable penetrance(80%) - AR (20%)
![Page 36: Humoral Immunodeficiencies](https://reader035.vdocument.in/reader035/viewer/2022062503/589df9161a28ab1e718b5705/html5/thumbnails/36.jpg)
CVID: genetic defects
Arthritis Research & Therapy 2012
![Page 37: Humoral Immunodeficiencies](https://reader035.vdocument.in/reader035/viewer/2022062503/589df9161a28ab1e718b5705/html5/thumbnails/37.jpg)
British journal of Hematology,2009
Clinical manifestations
![Page 38: Humoral Immunodeficiencies](https://reader035.vdocument.in/reader035/viewer/2022062503/589df9161a28ab1e718b5705/html5/thumbnails/38.jpg)
Blood,2008
![Page 39: Humoral Immunodeficiencies](https://reader035.vdocument.in/reader035/viewer/2022062503/589df9161a28ab1e718b5705/html5/thumbnails/39.jpg)
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
![Page 40: Humoral Immunodeficiencies](https://reader035.vdocument.in/reader035/viewer/2022062503/589df9161a28ab1e718b5705/html5/thumbnails/40.jpg)
• 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?
![Page 41: Humoral Immunodeficiencies](https://reader035.vdocument.in/reader035/viewer/2022062503/589df9161a28ab1e718b5705/html5/thumbnails/41.jpg)
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
![Page 42: Humoral Immunodeficiencies](https://reader035.vdocument.in/reader035/viewer/2022062503/589df9161a28ab1e718b5705/html5/thumbnails/42.jpg)
Selective IgA deficiency
![Page 43: Humoral Immunodeficiencies](https://reader035.vdocument.in/reader035/viewer/2022062503/589df9161a28ab1e718b5705/html5/thumbnails/43.jpg)
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
![Page 44: Humoral Immunodeficiencies](https://reader035.vdocument.in/reader035/viewer/2022062503/589df9161a28ab1e718b5705/html5/thumbnails/44.jpg)
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
![Page 45: Humoral Immunodeficiencies](https://reader035.vdocument.in/reader035/viewer/2022062503/589df9161a28ab1e718b5705/html5/thumbnails/45.jpg)
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
![Page 46: Humoral Immunodeficiencies](https://reader035.vdocument.in/reader035/viewer/2022062503/589df9161a28ab1e718b5705/html5/thumbnails/46.jpg)
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
![Page 47: Humoral Immunodeficiencies](https://reader035.vdocument.in/reader035/viewer/2022062503/589df9161a28ab1e718b5705/html5/thumbnails/47.jpg)
Lancet, 1985
![Page 48: Humoral Immunodeficiencies](https://reader035.vdocument.in/reader035/viewer/2022062503/589df9161a28ab1e718b5705/html5/thumbnails/48.jpg)
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
![Page 49: Humoral Immunodeficiencies](https://reader035.vdocument.in/reader035/viewer/2022062503/589df9161a28ab1e718b5705/html5/thumbnails/49.jpg)
Allergic disorder
Autoimmune conditions (Commonest after infections)Idiopathic thrombocytopenic purpuraHemolytic anemiaJuvenile rheumatoid arthritisThyroiditisSystemic lupus erthematosus
Malignancies
Clinical Manifestations
![Page 50: Humoral Immunodeficiencies](https://reader035.vdocument.in/reader035/viewer/2022062503/589df9161a28ab1e718b5705/html5/thumbnails/50.jpg)
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.
![Page 51: Humoral Immunodeficiencies](https://reader035.vdocument.in/reader035/viewer/2022062503/589df9161a28ab1e718b5705/html5/thumbnails/51.jpg)
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