Failures of the Immune System-Immunodeficiency

1. Phagocyte cell function

2. Complement protein

3. B-cell development/ function

4. T cell development/ function

5. Combined B- & T- cell deficiencies

Enumerate the Primary Immunodeficiencies

1. Chronic Granulomatous Disease (CGD)

2. Chediak-Higashi Syndrome

3. Leukocyte adhesion deficiency (LAD)

4. Glucose-6-Phosphate dehydrogenase (G6PD) deficiency

5. Myeloperoxidase deficiency

Enumerate the Phagocyte-Deficiency Diseases

1. C1sINH - Hereditary Angioedema

2. C2 - Increased incidence of Connective tissue disorder (SLE)

3. C1/C4/C2- Opsonization not efficient (LAD)

4. C3- Increased susceptibility to pyogenic infection

5. C5-8- Recurrent Neisseria infection

Enumerate the Complement Deficiencies

1. Bruton X-linked hypogammaglobulinemia

2. Transient Hypogammaglobulinemia of infancy

3. Common variable (acquired) hypogammaglobulinemia

4. Selective Ig deficiency (dysgammaglobulinemia)

Enumerate the B-cell deficiencies

1. Di George syndrome

2. Chronic mucocutaneous candidiasis

Enumerate the T-cell deficiencies

1. Adenosine deaminase (ADA) deficiency

2. Severe combined immunodeficiency disease (SCID)

3. Wiskott-Aldrich Syndrome

4. Ataxia-telangiectasia

Enumerate the Combined B & T cell deficiencies

Chronic Granulomatous Disease

• Deficiency of NADPH oxidase; failure to generate superoxide anion, other O2 radicals

• Recurrent infections w/ catalase-positive bacteria & fungi

Chediak-Higashi Syndrome

• Granule structural defect

• Recurrent infection with bacteria; chemotactic & degranulation defects; absent NK activity; partial albinism

Leukocyte adhesion deficiency (LAD)

• Deficiency of CD18 = chain of 2 integrins; LFA-1, complement receptor (CR3), CR4

• Recurrent infection w/ extracellular bacterial pathogens because of defective opsonization, adhesion, mobilization & Chemotaxis

Glucose-6-Phosphate dehydrogenase (G6PD) deficiency

• Deficiency of essential enzyme in hexose monophosphate shunt

• Same as CGD

Myeloperoxidase deficiency

• Granule enzyme deficiency

• Mild/ none

Hereditary Angioedema

Increased incidence of Connective tissue disorder (SLE)

Opsonization not efficient (LAD)

Increased susceptibility to pyogenic infection

Recurrent Neisseria infection

C1sINH -

C2 -

C1/C4/C2 -

C3 -

C5-8 -

B-cell Deficiencies

• Recurrent pyogenic infection w/ extracellular pathogens

• (-) Ig for opsonization & Complement activation

• T cell = intact

Bruton X-linked hypogammaglobulinemia

X Linked agammaglobulinemia

Tonsils and Adenoids

• X-linked recessive

• First appear in childhood (>6 months)

• ___&___ are atrophic

• Immunologic findings

  • Low immunoglobulin: all

  • No circulating B cells

  • Pre-B cells in the BM

• Primary defect: a block in maturation of the B cell due to a

  deficiency of a tyrosine kinase

Pneumococci, Streptococci, Meningococci, Pseudomonas, and H. influenza

Bruton X-linked hypogammaglobulinemia or X Linked agammaglobulinemia’s Recurrent bacterial infection with?

Transient Hypogammaglobulinemia of Infacy

• Delayed onset of normal IgG synthesis (sometimes IgA and M too)

• Seen in the 5ᵗʰ – 6ᵗʰ month of life

• Usually resolves by 16-30 months (2-4 years old)

• Normal B cell numbers, just delayed activation/maturation

• May have mild to moderate infections: otitis media, sinusitis, URTIs

• Maybe mistaken for XLA early on

Common variable (acquired) hypogammaglobulinemia

• Immunoglobulin levels decrease with time

• First appear in late teens to early 20s

• Associated w/ autoimmunity in the patient or in the family

• A syndrome that is probably several different diseases

• Low immunoglobulins = any class

• B cells present in the peripheral blood

Selective Ig deficiency (dysgammaglobulinemia)

• Several different diseases described

• Selective IgA deficiency is the most common

  • Repeated sinopulmonary infection, gastrointestinal disease

  • Many w/ IgA deficiency have no symptoms

  • If both IgA and IgG2 subclass deficiencies, more likely to have infection

T-cell deficiencies

• Px presents w/ viral/fungal infections

• B-cell function: compromised by lack of T-cell help

• Major defect: handling intracellular pathogens

• Px’s receiving immunosuppressive drugs for treatment of allograft may have similar problems with these organisms.

Di George syndrome

• Failure of development of third & fourth pharyngeal pouches

  • Hypoplasmic thymus

  • Hypoplastic parathyroid glands

• Clinical features

  • Thymic apalsia

  • Recurrent viral & fungal infections

  • Hypoparathyroidism – hypocalcemic tetany

  • Cardiac anomalies

  • Facial anomalies (fish mouth & flat face)

Chronic mucocutaneous candidiasis

Severe chronic skin & mucous membrane infections w/ the fungal pathogen Candida

albicans

Combined B & T cell deficiencies

• Susceptible to bacterial, viral & fungal infections

• T cell def predominates

Adenosine deaminase (ADA) deficiency

• 1ˢᵗ human disease successfully treated w/ gene therapy

• Normal rxn : Deoxyadenosine Deoxyinosine (non-toxic)

• ADA deficiency: Deoxyadenosine Phosphate leads to lymphocyte toxicity → apoptosis of T, B, and NK cells

• Key Features

  • Severe lymphopenia (↓ T, B, and NK cells)

  • Early-onset infections: bacterial, viral, fungal

  • Failure to thrive, chronic diarrhea

  • Treatment

Severe Combined Immunodeficiency Disease (SCID)

• X-linked & Autosomal

• Early infancy (3 months)

• B & T cells: does not function

• Pneumocystis pneumonia; most common

• Deficiencies:

  • Class I & II molecules

  • T cell receptors

  • Cytokine receptors

  • Signal-transduction

Wiskott-Aldrich Syndrome (X-linked)

• Mutation in WAS gene → defective actin cytoskeleton reorganization, Affects T cells, B cells, and platelets

• Inability to mount an IgM response to the capsular polysaccharide of bacteria, such as pneumococci

• Key Triad:

  • Recurrent infections (↓ T and B function)

  • Eczema (eczema-like dermatitis)

  • Thrombocytopenia (small platelets →petechiae, bleeding)

Ataxia-Telangiectasia

• Develops 1-2 years of age

• Sinopulmonary infections

• Autosomal recessive

• Ataxia: uncoordinated muscle movements

• Telangiectasia: dilation of small vessels; seen in sclera of eye

• Immunodeficiency

  • Selective IgA deficiency

  • Cell-mediated defects- variable

  • Other immunoglobulin- varaible