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Primary Immunodeficiency
Nishitha A 4TH Term
Objectives
WHAT WILL I LEARN TODAY?
Immunodeficiencies: Definition, cause and typesPrimary Immunodeficiencies: Definition, types, diagnosis and therapyExamples:SCID, XLA, DiGeorge’s syndrome, Ataxia-teleangectesia, Wiskott-Aldrich syndrome, CGD
Immunodeficiency
• Immune system’s ability to fight infectious diseases is completely absent or compromised.
• Types:Primary ImmunodeficiencySecondary Immunodeficiency
Immunodeficiency
• Cause for Immunodeficiency:Human Immune system:Very specificDependent on memory of cells and
lymphocytes that recognise foreign antigen and infected cells respectively.
• Any alterations in these functions Immunodeficiency.
Classification
•Most are genetically determined
•Less common
•May arise as complications of cancers, infestations, malnutrition, or side effects of immunosuppression, Irradiation and chemotherapy.
•More common
Primary Immunodeficiency
SecondaryImmunodeficiency
Primary Immunodeficiencies
• A group of disorders characterized by an impaired ability to produce normal immune response.
• Cause: mutations in genes involved in the development and function of immune organs, cells, and molecules.
• Genetically determined.• Usually diseases of infancy & childhood.
Primary Immunodeficiency
• Most important feature:• High Incidence in Males: Why ?• 6 X-linked ID’s have been
described:
5 - Affect Lymphocytes
1- Affect Phagocyte
Table 1. Characteristic infections of the primary immunodeficiencies
component primary pathogen primary site clinical example
T-cells intracellular, bacteria viruses, protozoa, fungi, non-specific SCID, DiGeorge
B-cells
pneumococcus,streptococcus, haemophilus
lung, skin, CNS IgG, IgM deficiencyIgG, IgM deficiency
enteric bacteria and viruses GI, nasal, eye IgA deficiency
phagocytesStaphylococcal,
Klebsiella Pseudomonas,
lung, skin, regional lymph node
Chronicgranulomatous disease (CGD)
complementneisseria, Haemophilus,
pneumococcus, streptococcus
CNSlungskin
C3, Factors I and H, late C omponents
Severe Combined Immunodeficiency(SCID)
• Synonyms: Glanzzman-Rinker syndrome, Bubble Boy Disease, Thymic Alymphoplasia
• Genetic disorder characterised by absence of T-lymphocytes.
• Impairment of both cellular & humoral response
• Specific defects in antigen presentation & functional immune molecules.
Bubble Boy
SCID-Types
• Main Types:Autosomal recessive (-ve T & B cells)X-linked recessive(+ve B cells)• Other important types:Nezelof SyndromeSCID associated with ADA & PNP deficiency.
Features of SCID
• Absent tonsils• Small or absent lymph nodes• Absent thymic shadow• Lymphopenias• Decreased Number of T cells• Severe agammaglobulinemia (Swiss type of
agammaglobulinemia)• No IG’s usually present
Thymic Dysplasia
.
Cell-Mediated/T cell Immunity
Bruton’s X-linked Agammaglobuinemia
• Primarily B-cell defect• Boys-more affected• Severe reduction in γ-globulins• IG’s, circulating and marrow B-cells.• Probable cause: Molecular defect at
Xq22.Mutation of bruton tyrosine kinase.• Therapy: IV IG’s.
DiGeorge’s syndrome
• Also called thymic hypoplasia• Congenital disorder• Abnormalities in structure derived from 3rd
and 4th pharyngeal pouches• Predominantly T cell defect• Charactersitics: Neonatal tetany(absence of
parathyroid)• Therapy: Thymic transplants
• Cleft palate
• Antimongoloid eyes
• Short philtrum with
fish-mouth appearance ,
• Micrognathia
• Low set pixie-like ears
• Short palpebral fissures
Facial features of children with DiGeorge syndrome
DiGeorge Syndrome
DiGeorge syndrome
Ataxia-telangiectasia
• Autosomal recessive• Incidence: 25:10,00,000• Characteristics: Progressive cerebellar ataxia,
ocular and cutaneous telangiectasias, severe sino-pulmonary infections, progeric changes, sclerodermoid changes
• Thymus: fetal-like histological pattern.• Translocation between 14 and 7
Ataxia
telangiectasia
Wiskott-Aldrich Syndrome
• X-linked condition• Incidence: 4:10,00,000• Severe eczema, recurrent infections, Bloody
diarrhea, chronic otitis• T cells appear bald :?• Platelets: Decreased in number, small• Failure to recognise polysaccharide antigens.• Defect: Failure in expression of sialophorin.
Eczema
Histological Pictutre:
Chronic Granulomatous Disease
• Incidence:1:10,00,000• Defect: Inability of phagocytes to produce
superoxide ineffective reduction of O2.• Failure to express respiratory burst associated
with phagocytosis.• Central necrosis and granulomatoid response in
lung, liver, bone , skin and lymph nodes.• Presence of numerous pigmented macrophages.
CGD patient with skin infectionsdue to Serratia marcescens
Chediak-Higashi Syndrome
• Rare autosomal disorder• Abnormal large granules in leucocytes leading to:– hypopigmentation/partial albinism– severe immunodeficiency– neurologic abnormalities– mild bleeding tendencies
• Defective gene: CHS1
Leucocyte-Adhesion defect
• Autosomal recessive disorder• Inability of phagocytic cells to adhere to
endothelial cells and migrate to infected sites• Characteristics: delayed cord dehiscence and
scar formation, recurrent diarrhea and respiratory symptoms, leucocytosis
• Defect in CD18 gene• Treatment: Bone marrow transplantation
Other Primary ID’s
• Selective IgA deficiency• Common variable Immunodeficiency• X-linked lymphoproliferative disease• Job’s syndrome
Complement deficiencies
• Involves 19 proteins: 11-classical, 3-alternate, 5-regulatory• Alteration in the expression of these proteins
Autoimmune & Immunodeficiency diseasesClassical AI affecting vessels & glomeruli
Alternate Pyogenic infections
Regulatory Hereditary Angioneurotic edema
Diagnosis of Primary Immunodeficiencies
• Histopathology• Immunohistochemistry• Monoclonal Antibodies• Cell separation by flow cytometry• Insitu Hybridisation
Therapy
• Supportive therapy- antibiotics• Replacement therapy-IV immunoglobulin
infusion, ADA-rich RBC infusions• Definitive therapy- Fetal thymic grafts, bone
marrow transplantation• Stem-cell therapy• Gene therapy
Thank you