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primary defect in antibody production.pptx
1. Primary Defects of Antibody
Production
PRESENTER : DR. IRA KC
MODERATOR: DR. SANTOSH GAUTAM
2. IMMUNE SYSTEM:
complex network of organs, cells and proteins that
defends the body against infection, whilst
protecting the body's own cells
Protects against pathogen
Check on auto-immunity
Cancer surveillance
IMMUNODEFICIENCY:
Inability to produce an adequate immune response
because of an insufficiency or absence of antibodies,
immune cells, or both
Increased susceptibility to infection
Increased risk of autoimmunity/rheumatologic
disorder
Increased predisposition to malignancy
6. IMMUNODEFICIENCY
Primary
Abnormalities in development of immune
mechanisms
Disorders of Humoral Immunity-affecting B
cell differentiation and antibody production
Disorders of Cellular Immunity-T cell
defects
Combined T cell and B cell defects
Phagocytic Defects
Complement Deficiencies
Secondary
Consequences of disease, drugs, nutritional
inadequacies & other processes interfere with
proper functioning of mature immune system
EG : HIV
: Nephrotic syndrome
7. December
21, 2023
Disorders of Humoral Immunity
(Antibody production)
1) X-linked Agamma - globulinemia ( Bruton’s Agamma-globulinemia, BTK deficiency, X-LAG)
2) Common Variable Immunodeficiency (CVID)
3) Selective IgA deficiency
4) Transient Hypo-gammaglobulinemia of Infancy
5) Immunodeficiency with hyper-IgM
6) X- linked lymphoproliferative disease
8. X-linked (Bruton’s) Agammaglobulinemia
1:200,000 live births,
1st immunodeficiency disease recognised. Described by Bruton (
1952 )
Genetic features: x-linked recessive inheritance, males.
Pathogenesis: abnormal gene XLA maps to q22 on the long
arm of the X chromosome, encodes the B-cell protein tyrosine
kinase Btk (Bruton tyrosine kinase).
Helps in signaling and maturation of pre B cell.
No/few B cells (pan hypogammaglobinemia), normal T cells
9. Clinical Features
Boys, remain well till first 6-9 months of life
Infections with extracellular pyogenic organisms , Mycoplasma
Chronic fungal infections are seen; Pneumocystis jiroveci pneumonia rarely occurs
Viral infections handled normally, except hepatitis viruses and enteroviruses
Paralysis after live polio vaccine
Failure to thrive
A boy with recurrent pneumonia absent tonsils/ no palpable Lymph
Nodes + positive family history
Order serum immunoglobulin level
10. Diagnosis
Serum concentrations of IgG, IgA, IgM, and IgE are far below 95% confidence
limits for appropriate age- and race-matched controls
Total Immunoglobulins :<100mg/dl
Flow cytometry: Absence of circulating B cells
Mature B cells (CD19,CD20,BCR) absent in peripheral blood
Under developed germinal centers of lymph nodes
11. Common Variable Immunodeficiency
Hypogammaglobinemia with phenotypically normal B cells
Age : 2nd -3rd decade of life
Sex: M=F
Recurrent pneumonia /sinusitis/ chronic diarrhea
Phenotypic diagnosis with a polygenic inheritance
Mutated (< 10 % case) ICOS, SH2DIA, CD19, CD20, CD21, CD81, BAFF-R, TACI
similar clinically with XLA
(except that enterovirus meningoencephalitis is rare )
Association with other autoimmune disease : high
14. Transient Hypogammaglobulinemia of Infancy
Represents developmental delay in the production of immunoglobulin
Most infants begin to produce IgG in the 1st 3 months, increases throughout infancy
Small number either begin late or do not increase their production as expected
Characterized by
Frequent sinopulmonary infections
Low serum immunoglobulins
Condition may last into pre-school years
Diagnosis can only be made definitively in retrospect
key distinction : responses to vaccines preserved.
Source of Diagnostic confusion
15. 15
Care and Treatment of the Child with Suspected
Transient Hypogammaglobinemia
Serial monitoring of immunoglobulins and antibody titers
Re-immunization may be necessary
Awareness that infections may require longer courses of antibiotics for treatment than
usually prescribed
Gamma globulin is seldom necessary
Any fever of 101.5F or greater requires that the child have a CBC, blood culture and
physical exam
Live viral vaccines should be held until immuno-competency is demonstrated
16. Selective IgA Deficiency
Most Common in this group
incidence 0.33% in normal populations.
Immunological features:
Serum IgA<5mg/dl but normal IgM and IgG
Genetic features : IgA Deficiency and genetic
factors: associated with HLA-A2, B8 and DW3 or A1 and B8
Pathogenesis: failure in terminal differentiation of B cells due to intrinsic B cell defect or abnormal T
cell help (TGF-B,IL-5) or in B cell responses to these cytokines
17. Selective IgA Deficiency
Clinical Features:
Majority are asymptomatic
Anaphylactic transfusion reactions
Atopic disorders
Recurrent infections in respiratory tract, Gastrointestinal tract, urogenital tract.
Diagnosis cannot be made until about 4 years of age, when IgA levels should be matured to adult levels
Treatment:
Washed erythrocytes (frozen blood would have this done routinely) or blood products from other IgA-
deficient individuals should be administered to patients with IgA deficiency.
IVIG not recommended
Not very severe
life threatening
18. Hyper IgM syndrome
Genetically heterogeneous
Characterized by Normal/Elevated serum IgM levels associated with Low/Absent IgG, IgA, and IgE
serum levels defect in the class switch recombination (CSR) process
Causative mutations identified in the CD40 ligand gene ( X chromosome) and 3 genes on autosomal
chromosomes: AID(Activation induced cytidine deaminase), UNG(Uracil DNA glycosylase) and
CD40 gene on chromosome 20.
All patients should undergo molecular analysis to ascertain the affected gene for purposes of genetic
counseling, carrier detection, and decisions regarding definitive therapy.
19.
20.
21. X-linked Autosomal Recessive
Gene mutation CD40 ligand gene AID, UNG, CD40
Lymph node Abortive germinal centers with with
depletion of follicular dendritic cells
cells
Giant germinal centers filled with
highly proliferating B cells
Susceptibility to P.jiroveci
pneumonia
marked No
Treatment HLA identical Hematopoietic Stem
Cell Transplantation, Granulocyte-
CSF
IVIg infusion, Antibiotics
22. X-linked Lymphoproliferative Disease
Also known as Duncan Disease
Two types namely ; XLP Type I AND XLP Type II
XLP Type I:
mutation in SH2D1A gene (encoding SAP)
Can lead to uncontrolled cytotoxic T-cell response to EBV
XLP Type II:
mutation in XIAP gene
23. Clinical Presentation
Fulminant Infectious Mononucleosis:
Excessive proliferation of EBV-infected B cells, cytotoxic T cells and macrophage in various tissues
including hematopoietic cells, brain, liver and heart massive infiltration of these cells into lymphoid
and other organs extensive parenchymal damage including hepatic necrosis and bone marrow failure
Thrombocytopenia, Anemia, hepatic dysfunction, meningoencephalitis, fulminant hepatitis
Dysgammaglobulinemia:
Decreased levels of IgG1 and IgG3 with elevated levels of IgM and IgA progress over time to include
deficiencies of all isotypes of Immunoglobulins
Lymphoma:
Due to impaired immune surveillance and elimination by T cells
24. Mean year of presentation: <5 yrs
Affected males are usually healthy until they acquire EBV infection
Asymptomatic until onset of complications
Unfavorable Prognosis
25. Treatment of humoral defects
Immunoglobulin administration (IVIG or SCIG)
at a dose of 400 mg/kg per month
EXCEPT FOR THE CD40 LIGAND DEFECT AND XLP stem cell transplantation
Judicious use of antibiotics to treat documented infections
26. Subcutaneous Immunoglobulin Replacement Therapy in Patients with Primary
Immunodeficiency in Routine Clinical Practice: The VISPO Prospective Multicenter Study
Alessandra Vultaggio, Chiara Azzari, Cinzia Milito, Andrea Finocchi, Claudia Toppino, Giuseppe Spadaro, Antonino Trizzino, Martire Baldassarr
Aim
To evaluate the shifting from intravenous immunoglobulins (IVIGs) replacement therapy to SCIG in patients with
primary immunodeficiency (PID) in a routine real-life situation.
Methods
In a multicenter prospective observational study, we enrolled 50 patients suffering from PID who were monitored for
24 months; 44 patients switched from IVIG and six from different SCIG preparations. The study preparation (human
IgG 16 %, Vivaglobin®, CSL Behring GmbH, Germany) was subcutaneously infused weekly (maximum volume
15 mL/site; maximum infusion rate 22 mL/h). The study endpoints were: annual rate of severe bacterial infections
(SBIs), local adverse reactions, quality of life, days off school/work, and days of hospitalization
Results
Thirty-three of 39 (84.6 %) patients who completed the study experienced an infection or signs thereof. Only five
SBIs were observed, corresponding to an annual rate of 0.056 episodes per patient in 44 subjects [intention-to-treat
(ITT) population]. A significant decrease in both days of hospitalization (1.93 ± 4.08 vs. 0.64 ± 2.94) and days off
school/work (15.27 ± 23.17 vs. 2.26 ± 4.45) was recorded at 24 months.
27. Local reactions were observed in 14/50 (28 %) patients, mainly consisting of skin manifestations at the injection site.
Only three (6.8 %) patients discontinued due to infusion site reactions. In patients shifting from IVIG to SCIG, the
total mean score of Life Quality Index (LQI) improved from 76.9 ± 16.8 to 90.7 ± 11.6 (P < 0.01) at 6 months; there
was an improvement also in the overall patients’ evaluation.
Conclusions
A total of 93.2 % patients tolerated the new route of administration and reported a significant improvement in their
LQI. Our results from a routine clinical practice in a real-life population are consistent with those of phase III
clinical studies.
