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

Introduction. Immunodeficiency diseases are : A diverse spectrum of illnesses due to various abnormalities of the immune Immunodeficiency diseases are : A diverse spectrum of illnesses due to various abnormalities of the immune Prevalence : Prevalence :  Primary (congenital) 1 : 10,000 to 1 : 200,000 present at birth.  Secondary (acquired) is more common.

Overview of Immunodeficiency Disorders. The defect might be In the level of stem cell or in any other level of tree

Clinical manifestations. ( is increased susceptibility to infections ) The patient is considered to have I.D. if the 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. Important : Early diagnosis & management reduce morbidity (disease).

Classification : Primary (congenital). Secondary (acquired). Its common Genetic mutations. Genetic polymorphism. They could be : either Monogenic ( defect in one gene ) or polygenic ( defect in more than one gene ) malnutrition. Most important cause viral & bacterial infections. e.g. AIDS which is caused by HIV Immunosuppressive drugs. (corticosteroids). For long-time use, it’ll depress the immune system excessive protein loss, burns, nephrotic syndrome ( loss of cells like RBC and loss of protein liek Ig )

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.

The severe combined immunodeficiency is characterized by effecting both B- and T- cells

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 Properties of B-cell defects

2.X- linked disease : If heterozygous If heterozygous Female carriers are normal. Female carriers are normal. Males manifest the disease. Males manifest the disease. 3.Severity of the disorder parallels ( is Proportional to ) the degree of the deficiency.

] FEATURES OF B-CELL DEFECT [ - Reduced B-cell counts to 0.1 percent ( normally 5-15 percent.) -Absence of Immunoglobulins. -Small Lymph nodes, no germinal centers ( the home of B-cells in the lymph node )

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

IMPORTANT Patients with B-cell defects are subject to: Recurrent bacterial infections Recurrent bacterial infections but Display normal immunity to most viral & fungal infections. because : T-cells are unaffected. T-cells are unaffected. Because T-cell which stands in the face of viral and fungal infection

Is the first I.D. Recognized in (1952) The most common ( 80 to 90 percent ) Defect in Bruton tyrosine kinase enzyme (BTK). The Defect involve a block in maturation of pre- B- cells to mature B- cells in bone marrow. Pre B-cell + BTK enzyme  Mature B-cell ( The disease ) ( the level of defect ) ( the result ) 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, ( conjunctiva, throat, skin, ear, bronchi & lung) bronchi & lung ) Infecting microbes include :- Pneumococci, H.influenzae Pneumococci, H.influenzae Streptococci. Streptococci. Also the patient is susceptible to certain viruses ( polio) and intestinal parasites (giardia ). and intestinal parasites (giardia ). X-linked agammaglobulinaemia. (XLA).cont..

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

Most are asymptomatic, but have increased rate of ( respiratory tract infection R.T.I ) Some have recurrent R.T.I. and G.I.T. Symptoms Because of  lack of secretion of IgA on the mucous membrane of GIT and respiratory tract Because of  lack of secretion of IgA on the mucous membrane of GIT and respiratory tract. ] Increased incidence of allergic manifestations [ anti - convlusant drugs (phenytoin) may cause secondary deficiency ( these drugs are used to treat epilepsy, they destroy IgA ) 2. Selective immunoglobulin deficiency. 1. IgA deficiency (1:700)

Characterized by : Characterized by : - - Low IgG, IgA & IgE - - Markedly elevated IgM - - High levels of autoantibodies (against neutrophils, platelets, red cells ) (against neutrophils, platelets, red cells ) ] So, low levels of RBCs, neutrophils, and platelets [ Recurrent infections especially Recurrent infections especially Pneumocystis carinii Pneumocystis carinii ]Pneumocystis carinii usually found in people who have AIDS[ ]Pneumocystis carinii usually found in people who have AIDS[ X- linked hyper-IgM Syndrome.

Defect in the CD 40L in T- cells lead to : Defect in the CD 40L in T- cells lead to : ( CD 40L is the hand that Th cell use it to shake other cells hands ) * No co-stimulatory signal for B-cells. * No co-stimulatory signal for B-cells. * No response to T-dependent antigens. * No response to T-dependent antigens. * No class – switching. * No class – switching. ( The change of one class of Ig to another one ) * No memory cells. * No memory cells. * Marked lymphadenopathy. * Marked lymphadenopathy. X-linked hyper-IgM Syndrome. (cont.) هاااااااام جدا جدا

( The disease ) ( the level of defect ) ( the result ) 3. X-linked hyper-IgM defective CD40 markedly Syndrome. Ligand. elevated IgM.

Management of immunoglobulin deficiencies : repeated intravenous immunoglobulin (IV Ig) reduces infectious complications. --- GIVE Ig ---

T- cell defects.

( congenital thymic aplasia ) First described in 1952 Characterized by : - Absence of the Thymus gland. ( So, no T-cells in the body ) - Hypoparathyroidism Which lead to tetany - Cardiovascular abnormalities and Characteristic facial features ] Because they appear from the same embryologic origin of the thymus ( 3-4 pharyngeal pouches) so they are involved[ ] Because they appear from the same embryologic origin of the thymus ( 3-4 pharyngeal pouches) so they are involved[ 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. ( Because of no T-cell ) So : 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 ). There’s a little number of circulating T-cell but B-cells are normal 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. ( graft versus host ) Reactions G.V.H. Reactions : the transplanted thymus or bone marrow recognize the host body cells as foreign body’s cells and attack it DiGeorge syndrome ;

Severe combined immunodeficiency. (SCID ). Both T and B cells are defected

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 immunodeficiency (SCID ) : in Autosomal recessive SCID - ADA deficiency. toxic metabolites in T & B-cells. - PNP deficiency. ( ADA and PNP are missing enzymes) Lead to

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

Leukocyte defects. Its either : Quantitative. ( amount ) Qualitative. ( function )

1. Congenital agranulocytosis : ] Kostmann syndrome [ G-CSF Defect in the gene inducing G-CSF (granulocyte colony stimulating factor) it is a stimulatory factor that acts on bone marrow to produce WBCs, so if its defected, the amount will decrease Features: pneumonia,otitis media, gingivostomatitis perineal abscesses Management: Respond to G-CSF therapy ( gene 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 ) immune-complex diseases lead to immune-complex diseases which can cause significant pathology in autoimmune diseases. ] N.B : immune-complex = antibody - antigen interaction [

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

The main component that needs to be activated is C3, All pathways activate C3 C3 then activates C5 and divide into C3a and C3b C5 then activate ( membrane - attack complex) and divide into C5a and C5b In classic pathway : C1 activates  C2 which activates  C4 finally activates  C3 C3 lactinclassic alternative

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

5.Deficiency of C3 ( the central point of complement ) ] no complement proteins [ Lead to infections with pyogenic bacteria. impaired clearance of immune-complexes..

C1 - inhibitor deficiency: hereditary angioedema

C1 - inhibitor deficiency: ( hereditary angioedema ) Is a deficiency of an enzyme which is responsible for prevention of ] C1 self-activation[ because it’ll attack the body’s own cells, and cause inflammation usually in the ]uvula[ which leads to choking till death. So these patients always have adrenaline in their pockets to prevent the swallowing only So the enzyme makes C1 activated only against pathogens.

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 CH50 5. 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 counseling ) diagnosis ( important for genetic counseling )

to know which pathway activates the complement : we check C2 and C3 levels, if both are decreased, it means they have been used a lot, so it’s the classic pathway If C3 levels are the only reduced  means lactin or alternative pathway.

T-cell. HIV virus.

)Regarding(GM-CSF)choose the correct answer: used in bone marrow transplant