IMMUNDEFICIENCY DISEASES DR.RAJESH KUMAR R S

INTRODUCTION

Defence mechanism of the body impaired Repeated microbial infections Enhanced susceptibility to malignancy Specific – Humoral, Cell mediated Non specific – Phagocytosis and Complement

Immunodeficiency Diseases

Primary: Abnormalities in the development of immune mechanisms

Secondary: Consequences of disease, drug, nutritional inadequacies

CLASSIFICATION OF PRIMARY IMMUNODEFICIENCY SYNDROMES Humoral Immunodeficiencies

Cellular Immunodeficiencies Combined Immunodeficiencies Disorders of Complement Disorders of Phagocytosis

HUMORAL IMMUNODEFICIENCIES (B CELL DEFECTS)

X linked agammaglobulinemia Transient hypogammaglobulinemia of infancy Common variable immunodeficiency Selective Immunoglobulin deficiency Immunodeficiencies with hyper – IgM Transcobalamin II Deficiecy

X LINKED AGAMMAGLOBULINEMIA

Bruton’s disease Disease not apparent till 6 months of age Recurrent bacterial infection with Pneumococci, Streptococci,

Meningococci, Pseudomonas and H. influenza Patient respond normally to viral infections All classes of immunoglobulins are grossly depleted Tonsils and Adenoids are atrophic Depletion of cells in bursa depenent areas of Lymph nodes.

Marked decrease of B cells in circulation Antibody formation does not occur even after injection of antigen CMI is not affected Allograft rejection is normal Arthritis, haemolytic anemia and atopic manifestations 300 mg/Kg of Gamma globulin in 3 doses followed by monthly

injections of 100 mg/kg Whole Plasma infusion

TRANSIENT HYPOGAMMAGLOBULINEMIA OF INFANCY

Abnormal delay in Immunoglobulin G synthesis Maternal Ig G are catabolised by the second month. Recurrent Otitis media and Respiratory infections Spontaneous recovery occur between 18 and 30 months of age. Prophylaxis with Gamma globulin is not recommended

COMMON VARIABLE IMMUNODEFICIENCY

Late onset Hypogammaglobulinemia 15 – 35 years of age Recurrent pyogenic infection and increased incidence of

autoimmune disease. Malabsorption and Giardiasis The total immunoglobulin level is low Defective B cell in circulation Increased suppressor T cell and diminished helper T cell activity

SELECTIVE IMMUNOGLOBULIN DEFICIENCIES

Reported in 1% of all patients with recurrent infection Isolated Ig A deficiency reported in 0.2% of normal population Increased susceptibility to respiratory infections Steatorrhea Atopic disorders Anti IgA antibodies present Preventive antibiotics Selective Ig M deficiency associated with Septicemia

IMMUNODEFICIENCIES WITH HYPER IgM

X linked Autosomal recessive Low Ig A and Ig G levels are seen with elevated Ig M Infections Thrombocytopenia, Neutropenia, Hemolytic anemia and renal

lesions Congenital Rubella Intravenous Immunoglobulin therapy

TRANSCOBALAMIN II DEFICIENCY

Autosomal recessive Megaloblastic anemia Intestinal Villous Atrophy Depleted plasma cells Diminished immunoglobulin levels Impaired phagocytosis VITAMIN B12 treatment

CELLULAR IMMUNODEFICIENCIES (T CELL DEFECTS)

Thymic hypoplasia Chronic mucocutaneous candidiaisis Purine Nucleoside Phosphorylase deficiecy

THYMIC HYPOPLASIA (DIGEORGE SYNDROME)

Developmental defect Aplasia or Hypoplasia of the thymus and Parathyroid gland Not hereditary Intrauterine infection Fallot’s tetrology Neonatal tetany viral, fungal and bacterial infection

DIGEORGE SYNDROME

The thymus dependent areas of the lymph node and spleen are depleted of lymphocytes

Circulating T cells are reduced in number Delayed hypersensitivity and graft rejection are depressed Transplantion of fetal thymus tissue

CHRONIC MUCOCUTANEOUS CANDIDIASIS

Abnormal immunological response to Candida albicans Severe Chronic Candidiasis of mucosa, skin and nails Endocrinopathies CMI to candida is deficient Transfer factor + Amphotericin B

PURINE NUCLEOSIDE PHOSPHORYLASE DEFICIENCY

PNP degrades Purines to Hypoxanthine and finally to uric acid Increased dGTP levels Hypoplastic anemia Recurrent Pneumonia Diarrhea Candidiasis Low serum uric acid helps in diagnosis Allogenic Hematopoietic Stem Cell Transplantation

COMBINED IMMUNODEFICIENCIES

Nezelof syndrome Ataxia Telengiectasia Wiskott Aldrich Syndrome Immunodeficiency with Thymoma Episodic lymphopenia with lymphocytotoxin Severe combined immunodeficiencies

COMBINED IMMUNDEFICIENCIES

Nezelof Syndrome Ataxia telangiectasia Wiskott Aldrich Syndrome Immunodeficiency with thymoma Immunodeficiency with short limbed dwarfism Episodic lymphopenia with Lymphocytotoxin Severe combined immunodeficies

NEZELOF SYNDROME

Cellular immunodeficiency with abnormal immunoglobulin synthesis

Recurrent infections Abundant plasma cells are seen in the spleen, lymph nodes and

intestines Thymic dysplasia with lymphoid depletion Antigenic stimuli do not induce antibody formation Histocompatible bone marrow transplant, transfer factor &

Thymus transplantation Antimicrobial therapy

ATAXIA TELANGIECTASIA

Autosomal recessive Cerebellar ataxia Chorioatethoid movements Telengiectasia Ovarian dysgenesis Sinopulmonary infection & malignancy Absence of IgA & low IgE Transfer factor therapy and fetal thymus transplants

WISKOTT ALDRICH SYNDROME

X linked disease Eczema, thrombocytopenic purpura, recurrent infections Death due to infection, hemorrhage, lymphoreticular malignancy Cellular depletion of thymus and paracortical areas of lymph

nodes Low IgM levels Specific inability to respond to polysaccharide antigen

ECZEMA THROMBOCYTOPENIC PURPURA

IMMUNODEFICIENCY WITH THYMOMA

Adults Benign thymic tumour Impaired cell mediated immunity Agammaglobulinemia Aplastic anemia

EPISODIC LYMPHOPENIA WITH LYMPHOCYTOTOXIN

Episodic but profound depression of T cell function Complement dependent Lymphocytotoxin Anti lymphocyte antibody No immunological memory familial

SEVERE COMBINED IMMUNODEFICIENCIES

Autosomal recessive Primary defects are at the level of early precursors of

immunocompetent cells in the fetal liver and bone marrow Swiss type agammaglobulinemia Reticular dysgenesis of de Vaal Adenosine deaminase deficiency

RETICULAR DYSGENESIS OF DE VAAL

Multipotent hemopoietic stem cell Total failure of myelopoiesis Lymphopenia, neutropenia, thrombocytopenia, anemia and bone

marrow aplasia Invariably fatal in the first week of life

DISORDERS OF PHAGOCYTOSIS

Chronic Granulomatous Disease Myeloperoxidase deficiency Chediak Higashi Syndrome Leukocyte G6PD deficiency Job’s syndrome

DISORDERS OF PHAGOCYTOSIS

Tuftsin deficiency Lazy Leukocyte Syndrome Hyper- IgE syndrome Actin Binding Protein Deficiency Shwachman’s disease

Chronic Granulomatous Disease

Familial disease Recurrent infection with low grade pathogen (catalase +) Suppurative granulomatous lesions in skin and lymph nodes Hepatospleenomegaly Progressive infiltration in lungs Granulomatous Septic Osteomyelitis

Chronic Granulomatous Disease

NADPH Oxidase Engulfment of bacteria is not followed by activation of oxygen

dependent killing mechanisms Nitroblue tetrazolium test

CHEDIAK HIGASHI SYNDROME

Genetic disorder Decreased pigmentation of the skin, eyes and hair Photophobia Nystagmus Giant peroxidase positive inclusions in the cytoplasm of

leukocytes due to autophagocytic activity Diminished phagocytic activity Frequent and severe pyogenic infections

CHEDIAK HIGASHI SYNDROME

JOB’S SYNDROME

Multiple large Staphylococcal abscesses occurring repeatedly on the skin and in various organs with little inflammatory response

Atopic Eczema, Chronic Nasal discharge and Otitis media Elevated IgE

TUFTSIN DEFICIENCY

Leukokinin capable of stimulating phagocytosis Tetrapeptide Local and systemic bacterial infections

LAZY LEUKOCYTE SYNDROME

Defect in chemotaxis and neutrophil mobility Normal number of Neutrophils in Bone Marrow Peripheral neutropenia Poor leukocyte response to chemical and inflammatory

stimulation Bacterial infection Recurrent stomatitis, Gingivitis and Otitis

HYPER IgE SYNDROME

Early onset Eczema Recurrent bacterial infections such as abscess, Pneumonia and

secondary infections of Eczema Staphylococcus aureus Streptococcus pyogenes IgE levels are more than 10 times the normal level

SHWACHMAN’S DISEASE

InfectionPancreatitis

Decreased Neutrophil mobility

Bone abnormalities

SECONDARY IMMUNODEFICIENCIES

Malnutrition Malignancy Infection Metabolic disorders Cytotoxic drugs Humoral and cell mediated immune deficiency

HUMORAL DEFICIENCY

Chronic lymphatic leukemia Nephrotic Syndrome Exfoliative Skin disease Protein losing Enteropathies Multiple Myeloma

CELL MEDIATED IMMUNE DEFICIENCY

Hodgkin’s disease Obstruction in lymph circulation Lepromatous leprosy Measles

CLINICAL CASE

A nine month old infant was brought to the hospital with symptoms of fever and difficulty in breathing. The mother reported of two similar episodes in the previous two months. At the age of 12 months, the child was again brought in with an episode of measles, from which he recovered after treatment. At 18 months of age, it was observed that the boy’s height and weight were not appropriate to his age. The child was the fourth of unrelated parents. His 3 sisters enjoyed good health and the parents did not report of them suffering from any repeated infections, unlike the boy.

Tests on the boy showed the serum immunoglobulin G to be less than a tenth and IgA and IgM to be less than a hundredth of the normal level. Lymph node biopsy revealed depletion of cells of bursa dependent areas.

Diagnosis? Treatment?

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