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

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