Immunodeficiency diseases. Prof. Mohamed Osman GadElRab. College of Medicine & KKUH.

Introduction. * A diverse spectrum of illnesses due to * A diverse spectrum of illnesses due to various abnormalities of the immune various abnormalities of the immune system. system. Prevalence (primary) 1 in 10,000 to 1 in 200,000 Prevalence (primary) 1 in 10,000 to 1 in 200,000 ( live births. ). ( live births. ). (secondary immunodeficiency is more common ) (secondary immunodeficiency is more common )

Overview of Immunodeficiency Disorders.

Clinical manifestations. Increased susceptibility to infections. I.D. Is considered when infections are : Frequent & severe. Resistant to antimicrobial therapy. Caused by opportunistic Infections.

Since the main presentation is infection, It is critical to maintain an index of suspicion to diagnose I.D. Early diagnosis & management reduce morbidity.

Classification : Primary (congenital). Secondary (acquired). Genetic mutations. Genetic polymorphism. Monogenic or polygenic. malnutrition. viral & bacterial infections. immunosuppressive drugs. (corticosteroids). excessive protein loss, burns, nephrotic syndrome.

Primary or acquired. can affect. Natural immunity (non-specific body defenses). Acquired immunity. (specific body defenses). Phagocytic cells. Complement proteins. T-cells. B-cells.

T-cell. B-cell. Phagocytes. Combined T& B cells (SCID). SCID. T-cell. B-cell. Phagocyte.

B-cell defects. Gammaglobulinaemias:

1.Diverse spectrum of diseases ranging from: Complete absence of B-cells, Plasma cells and Immunoglobulin's to selective absence of certain immunoglobulin classes. Complete absence of B-cells, Plasma cells and Immunoglobulin's to selective absence of certain immunoglobulin classes. B-cell defects.

2 X- linked disease : Female carriers normal. Female carriers normal. Males manifest the disease. Males manifest the disease. 3. Severity of the disorder parallels the degree of the deficiency.

- Reduced B-cell counts to 0.1 percent ( normally 5-15 percent.) - Absence of Immunoglobulins. - Small L.nodes, no germinal centers

Early B-cell differentiation. Lesions can occur at any site in the pathway of B-cell development.

Patients with B-cell defects are subject to: * Recurrent bacterial infections. but * Display normal immunity to most viral & fungal infections. because : T-cells are unaffected.

*The first I.D. recognized (1952). *The most common 80 to 90 percent. *Defect in Bruton tyrosine kinase (BTK). *The Defect involve a block in maturation of pre- B- cells to mature B- cells in B.M.. 1. X-linked Bruton tyrosine no mature agammaglobulinaemia. Kinase (Btk) B-cells.

- Reduced B-cell counts to 0.1 percent ( normally 5-15 percent.) - Absence of Immunoglobulins. - Small L.nodes, no germinal centers. Features of XLA.:

Affected children suffer from recurrent pyogenic bacterial infections of : conjunctiva, throat, skin, ear, bronchi & lung. * Infecting microbes include : Pneumococci, H.influenzae Streptococci. * Also susceptible to certain viruses (polio.) and intestinal parasites (giardia ). X-linked agammaglobulinaemia. (XLA).cont..

* Most intracellular microbes & fungi are handled normally (T- cells normal ). X-linked agammaglobulinaemia. (XLA).cont..

* Most are asymptomatic. ( but have increased rate of (R.T.I.). * Some have recurrent R.T.I. an G.I.T. symptoms * Increased incidence of allergic manifestations. *anti- convlusant drugs (phenytoin) may cause secondary deficiency. 2. Selective immunoglobulin deficiency. 1. IgA deficiency (1:700)

Characterized by : Characterized by : - Low IgG, IgA & IgE. - Low IgG, IgA & IgE. - Markedly elevated IgM. - Markedly elevated IgM. - High levels of autoantibodies - High levels of autoantibodies to neutrophils, platelets, red cells. to neutrophils, platelets, red cells. Recurrent infections especially Recurrent infections especially Pneumocystis carinii. Pneumocystis carinii. X- linked hyper-IgM Syndrome..

Defect in the CD 40L in T- cells. Defect in the CD 40L in T- cells. * No co-stimulatory signal for B-cells. * No co-stimulatory signal for B-cells. * No response to TD antigens. * No response to TD antigens. * No class – switching. * No class – switching. * No memory cells. * No memory cells. * Marked lymphadenopathy. * Marked lymphadenopathy. X-linked hyper-IgM Syndrome. (cont.).

3. X-linked hyper-IgM defective CD40 markedly Syndrome. Ligand. elevated IgM.

Management of immunoglobulin deficiencies : *Periodic intravenous immunoglobulin (IVIG) reduces infectious complications.

T- cell defects.

(congenital thymic aplasia ) * First described in * Characterized by : - Absence of the Thymus gland. - Hyperparathyroidism. - Cardiovascular abnormalities. - Characteristic facial features. DiGeorge Syndrome :

Failure of the third & fourth pharyngeal pouches to develop. *Features : -Children may present with seizures ( tetany). -Extreme susceptibility to viral, protozoal, and fungal infections. 1. profound depression of T-cell numbers. 2. absence of T-cell responses. DiGeorge syndrome :

In some cases B-cells are normal and produce effective humoral immunity to bacterial infections. (Partial Di George Syndrome.) ( thymic hypoplasia, Nezelof syndrome ). * In some T-cell – dependant antibody production is absent.( no helper T- cells ). DiGeorge syndrome :

Management: Fetal thymus tissue graft (14 week old). steps should be taken to prevent G.V.H. Reactions. ( graft versus host ) DiGeorge syndrome ;

Severe combined immunodeficiency. (SCID ).

Features: 1. Increased susceptibility to viral, fungal, bacterial & protozoal infection. ( start at 3 month of age.) 2. Failure to thrive. 3. Reduced weight gain. 4. Prolonged diarrhea. 5. Moniliasis due to candida. Severe combined I.D. :

Severe combined Autosomal recessive SCID. immunodeficiency : (SCID ). - ADA deficiency. toxic metabolites in T & B-cells. - PNP deficiency.

Management of recessive (SCID.) 1. Infusion of purified enzymes. 2. Gene therapy.

Leukocyte defects. Quantitative. Qualitative.

1. Congenital agranulocytosis : Kostmann syndrome. Defect in the gene inducing G-CSF (granulocyte colony stimulating factor). Features: pneumonia,otitis media, gingivostomatitis perineal abscesses. Management: Respond to G-CSF therapy. Quantitative.

Phagocyte defects.

1.Defect in response to chemotactic agents. 2.Defect in intracellular killing. A. Defect in chemotaxis: Leukocyte adhesion deficiency (LAD.) Qualitative.

B. Defect in intracellular killing: 1.Chronic granulomatous disease: x-linked. (75%) autosomal recessive.(25%). DEFECT: in the oxidative complex. ( responsible for producing superoxide radicals.) FEATURES: Extreme susceptibility to infections. Granulomatous inflammation. (chronic T-cell stimulation.)

Complement deficiency.

Deficiency of all complement components have been described C1-C9. 1. Deficiency of C1, C2 & C4. ( classical pathway ) lead to immune-complex diseases which can cause significant pathology in autoimmune diseases.

Pathways of complement activation. CLASSICAL PATHWAY ALTERNATIVE PATHWAY activation Of C5 LYTIC ATTACK PATHWAY antibody dependent LECTIN PATHWAY antibody independent Activation of C3 and generation of C5 convertase

4. Deficiency of membrane - attack complex. (MAC). ( C5 - C9 ) Lead to infection with N.meningitides and N.gonorrhea.

5. Deficiency of C3.5. Deficiency of C3. Lead to infections with pyogenic bacteria. Lead to infections with pyogenic bacteria. impaired clearance of immune-complexes.. impaired clearance of immune-complexes..

C1 - inhibitor deficiency: hereditary angioedema

4. Laboratory evaluation. 1. Complete blood count.(total & differential). 1. Complete blood count.(total & differential). 2. Evaluation of antibody responses. 2. Evaluation of antibody responses. A. determination of serum immunoglobulins. A. determination of serum immunoglobulins. B. measure specific antibody responses: B. measure specific antibody responses: -To polysaccharide antigens. -To polysaccharide antigens. ( measure isohemagglutinins. ) ( measure isohemagglutinins. ) - To protein antigens. - To protein antigens. ( measure antibodies to tetanus.) ( measure antibodies to tetanus.)

3. Determination of T & B cell counts. ( by flow cytometry ) 3. Determination of T & B cell counts. ( by flow cytometry ) 4. Determination of the complement 4. Determination of the complement components. C3, C4. components. C3, C4. - assess functional activity by CH50. - assess functional activity by CH Assess phagocyte function. 5. Assess phagocyte function. - phagocytosis & respiratory burst. - phagocytosis & respiratory burst. 6. Carrier detection & prenatal 6. Carrier detection & prenatal diagnosis. ( important for genetic diagnosis. ( important for genetic counseling.) counseling.)

T-cell. HIV virus.