IMMUNODEFICIENCY DISORDERS

Host Defense Mechanisms Skin and mucosal barriers Humoral immunity (B cells, plasma cells, Ab) Cell-mediated immunity (T cells) Phagocytosis Complement

Classification of Immunodeficiency states Primary - intrinsic defect in immune system - many genes now identified. Secondary - known causative agent eg. HIV virus, drug

Immunodeficiency - when to suspect? INFECTIONS Recurrent – sinus, lungs abscesses; brain Atypical Atypical mycobacterium e.g. M. avium Opportunistic organisms eg. Pneumocystis carinii – in T cell defects Organisms that respond poorly to therapy Growth retardation Family history

Suspecting Immunodeficiency Humoral (antibody) deficiency associated with: Recurrent infections with encapsulated bacteria Chronic sinupulmonary infections Cell-mediated deficiency characterized by: Recurrent infections with Viruses Fungi Opportunistic organisms (PCP) Diarrhea, wasting, growth retardation Combined immunodeficiency

Many of these disorders also include abnormalities in the cells responsible for generating or maintaining an antibody response. The patients often improve with antibiotics but get sick again when these are discontinued. The cornerstone of therapy for antibody deficiency disorders is immunoglobulin (Ig) replacement.

Primary Immunodeficiency Version of lecture for Science students.

Primary Immunodeficiency Great advances in genetic identification in late 1980s, early 1990s Over 150 genetic disorders now recognised Selection of disorders presented here

Humoral Immunodeficiency (B cells) Transient hypogammaglobulinemia of infancy Slow to develop normal levels of antibody Asymptomatic, minor infections Low levels of IgG, IgA (IgM usually normal) Resolves by 3-6 yo IgA deficiency Most common humoral antibody deficiency 50-80% asymptomatic Recurrent sinopulmonary infections most frequent manifestation May have severe malabsorption (chronic diarrhea) Isolated low IgA level Increased risk of autoimmune disorders

Bruton’s X-linked Agammaglobulinemia No B cells Child clinically well for first 6 months of life Recurrent upper/lower respiratory tract infections with encapsulated bacteria (S. pneumo, H.flu) Bronchiectasis  chronic cough/increased sputum Sepsis, meningitis, skin infections Paucity of lymphoid tissue (tonsils, adenoids) Markedly decreased IgG, IgA, IgM Treatment: IVIG, antibiotic therapy

Bruton’s X-linked Agammaglobulinem- case history. BB - 25 year old male – unwell as child Lobar pneumonia x 3 Family history - 2 brothers died following recurrent lung infections Investigations - absence of antibodies - IgG, IgA, IgM DIAGNOSIS - X-linked agammaglobulinaemia BB- patient with XLA

Common Variable Immunodeficiency B lymphs don’t differentiate into plasma cells Recurrent sinopulmonary infections Low IgG, IgA, IgM Treatment: IV Ig Associated with autoimmune disease, lymphoma

Common variable immunodeficiency - case AB - 29 year old male Recurrent ear and sinus infections Strep. pneumoniae lung infection Malabsorbtion - Giardiasis lamblia infection DIAGNOSIS - Common Variable Immunodeficiency - CVID

Antibody deficiency – infection sites Otitis media Pneumonia - affecting right lower lobe

DiGeorge Syndrome No T cells secondary to thymic hypoplasia Overwhelming infections with viruses, fungi, bacteria Treatment: correct hypocalcemia, cardiac defects, fetal thymus transplant

SCID (severe combined immunodeficiency) Defects in stem cell maturation Manifestations seen in first 3 months of life Recurrent, severe bacterial, viral, fungal, and protozoan infections (usually respiratory infections) Failure to thrive, diarrhea, dermatitis, candidiasis Most have lymphopenia, decreased IgG, IgA, and IgM Diagnosis made by analysis of T, B, and NK cell subsets Treatment: isolation, treat underlying infections, bone marrow transplant

Case history 4 1 year old boy Recurrent chest infections - viral, fungal, bacterial Constantly in hospital Severe “failure to thrive” Blood tests - low lymphocyte count

T cell immunodeficiency Severe combined immunodeficiency - SCID 9 different molecular causes children living in gnotobiotic isolation, ie bubbles! 'david' who lived in isolation until he was 12; he then received a bmt from his sister, but died about 4 months or so later from an overwhelming ebv infection

SCID - treatment SYMPTOMS - Present early - by 3 months Oral candidiasis Lung inflammation “pneumonitis” Diarrhoea Failure to thrive !!! DIAGNOSIS Absence of T cells Some - absent B and/or NK cells Low immunoglobulins Medical Emergency Isolation - negative pressure environment Immunoglobulin replacement Bone marrow transplant - curative 80% Gene therapy - works but ……. leukaemia

Increased risk for hematologic malignancy Treatment: manage bleeding/infections, BMT

Ataxia Telangiectasia Autosomal recessive deficiency in DNA repair affecting T and B cells Progressive ataxia, telangiectasia, variable immunodeficiency (recurrent sinopulmonary infections common) Increased risk of malignancy (leukemia, lymphoma)

Hyper IgE (Job) syndrome Autosomal recessive Symptoms/signs Coarse facial features/skeletal abnormalities Recurrent staph infections Impetigo (resistant) Pneumonia with pneumatocele formation 3 E’s: Elevated IgE, Eosinophilia, Eczema

Hyper IgM Syndrome T cell abnormality preventing IgM  IgG X-linked recessive (males 6 mo-1 year) Frequent sinopulmonary infections, diarrhea, opportunistic infections (PCP) Low levels of IgG/IgA, high levels of IgM Treatment: Ig replacement

Case history 3-- Hyper IgM syndrome PO, aged 20 years Recurrent bacterial infections, early childhood Tuberculosis, disseminated aged 6 years Brother with similar history died from brain inflammatory disorder Diagnosis - Hyper IgM syndrome Absent IgG, IgA Fail to switch IgM to other Ig classes

Type of infection helps predict the type of immunodeficency B lymphocyte - pyogenic bacteria - lungs T lymphocyte - viruses, fungi, mycobacteria Complement - meningococcus - CNS Phagocyte - staphylococcus - skin

Antibody deficiency – infection sites Otitis media Pneumonia - affecting right lower lobe

CT scan of lung - bronchiectasis

Secondary immunodeficiency Multiple factors can affect immune function Age - reduced function in young, old Nutrition - dietary defects eg. iron deficient Developing world - malnutrition Other disease - eg. cancer Therapy - drugs, radiation Viruses - HIV, others

HIV Retrovirus infecting CD4 + cells Vertical transmission, breastmilk, sex Wide range of clinical manifestations Failure to thrive, fevers, night sweats, malaise, recurrent thrush, recurrent bacterial infections Decreased CD4 count, may have elevated Ig AZT x 6 weeks, PCP prophylaxis

Complement System Disorders Defects of early components (C1-C4) associated with infections with encapsulated bacteria Present similarly to humoral immune deficiencies Defects of late components (C5-C9) associated with Neisseria infections Also associated with autoimmune-like conditions CH50 functional assay assesses entire complement cascade Also may use individual components Treatment: treat infectious and autoimmune sequelae