Immunodeficiency Results from the absence, or failure of normal function of one or more elements of immune system. involve abnormalities of T or B cells, the cells of the adaptive immune system. or abnormalities of elements such as complements or phagocytes, which act on non-specifically in immunity

(genetically determined) Immunodeficiency can be divided into 1. Primary immunodeficiency disorders-congenital immunodeficiency (genetically determined) 2. Secondary immunodeficiency disorders (acquired immunodeficiency) Arise as complication of infection, malnutrition, aging, side effects of immunosuppressive drugs and irradiation

B-cell deficiency A. X- linked hypogamaglobunemia or (Bruton’s Agammaglobulinaemia) Failure of pre-B cells to differentiate into B cells. due to mutation in the gene encoding Tyrosine kinase an important signal transduction protein CMI is normal but very low levels of all immunoglobulin and absent of B cells in young boys Female carriers are immunologically normal

Present with pyogenic infections (S. aureus, S. pyogenes , S Present with pyogenic infections (S. aureus, S. pyogenes , S. pneumoniae, N.meningitides, H.influenzae ) which cause infection of the middle ear (otitis), sinuses (sinusitis) and lungs (pneumonia or bronchitis), But in some instances infections can involve the bloodstream or internal organs as well. Patients with XLA are prone to develop infections because they lack antibodies.

Most patients with agammaglobulinemia have very small tonsils and lymph nodes This is because most of the bulk of tonsils and lymph nodes is made up of B-lymphocytes. In the absence of B-lymphocytes, these tissues are reduced in size.

Diagnosis Agammaglobulinemia should be considered in any child with recurrent or severe bacterial infections, particularly if the patient has small or absent tonsils and lymph nodes. The first screening test should be an evaluation of serum immunoglobulins

If the serum immunoglobulins are low or if the physician strongly suspects the diagnosis of agammaglobulinemia, the number of B-cells in the peripheral blood should be measured. A low percentage of B-cells (nearly absent) in the blood is the most reliable laboratory finding in patients with either XLA pts with XLA can be given some of the antibodies that they are lacking.

B. Selective immunoglobulin deficiencies IgA deficiency characterized by an undetectable level of immunoglobulin A (IgA) in the blood and secretions but no other immunoglobulin deficiencies. Patients presents with weakened mucosal defenses thus; (a) recurrent sinus and lung infections (b) Diarrhea.

IgA deficiency is caused by the failure of heavy chain gene switching Pts with selective IgM and IgG also have recurrent pulmonary infection caused by pyogenic bacteria H. influenza S. pneumonia and S. aureus

T cell deficiency A. THYMIC HYPOPLASIA (DIGEORGES SYNDROME) Is a congenital malformation affecting the 3rd and 4th pharyngeal pouches. These structures give rise to the (1) Thymus (2) parathyroid glands and, (3) portion of the lip, ears, and aortic arch. Both thymus and parathyroid fail to develop properly.

The thymus is usually rudimentary and T cells are deficient or absent in circulation. Thus infants with this deficient are vulnerable to viral, fungal or protozoan infections. Also defects to the face, ears, heart and great vessels.

Transplantation of fetal thymus may reconstitute T cell immunity Management Transplantation of fetal thymus may reconstitute T cell immunity thymus from a child < 14 wks should be used to avoid Graft Versus Host (GVH) reaction

B. Chronic mucocutaneous candidiasis Skin and mucous membrane of children are infected with C.albicans which is non pathogenic member of normal flora. These children have T cell specific deficiency to this organism other T cell and B cells are normal. Treatment include antifungal drugs

C. HYPER IgM SYNDROME Present with recurrent pyogenic bacterial infection pts have high conc. of IgM but very little IgG, IgE & IgA They have normal number of B and T cells The mutation is in the gene encoding the CD40 ligand in the CD4 positive helper T cells

The T cell have defect in the surface protein (CD40 ligand) that interact with CD40 on the B cell surface. The failure to properly interact with CD40 result in inability of the B cells to switch from the production of IgM to other classes of antibodies recurrent pyogenic bacterial infections begins early in life Treatment- gamma globulin

D. Interleukin-12 Receptor Deficiency Interleukin-12 (IL-12) is involved in cellular immune responses against intracellular pathogens by promoting the generation of TH1 cells The absence of the receptor prevents IL-12 from initiating a Th-1 response, which is required to limit mycobacterial infections and lead to disseminated mycobacterial infections

Combined B cells and T cells deficiencies A. SEVERE COMBINED IMMUNODEFICIENCY (SCID) defects in both humoral and cell mediated response. infants are susceptible to: Severe infections (viral, bacterial, fungal and protozoa) Opportunistic infections with; candida , P. jeroveci, cytomegalovirus, pseudomonas. Occur in early infancy 3 months of age

In some children the B & T cells are absent in others the number of cells is normal but they do not function properly Immunoglobulin levels are very low and tonsils and lymph nodes are absent Pneumocysts pneumonia is the most common presenting infection in these infants infection caused by C .albicans and viruses such as varicella zoster and cytomegalovirus and respiratory cycytial virus are common and often fatal.

There are different forms of SCID; Cytokine receptor mutation form ADA deficiency (adenosine deaminase) Failure of expression of class II MHC molecule.

Cytokine Receptor Mutation Form Severe defect is in the T cell compartment, with secondary impairment of humoral immunity and IL-2,4,7,11,15 . patient have functional deficient of which are required for T cell development hence lack of T cells.

Adenosine deaminase (ADA) Deficiency; is caused by mutations in the ADA gene that provides instructions for producing the enzyme adenosine deaminase This enzyme is most active in lymphocytes which protect the body against harmful invaders, such as bacteria and viruses

The function of the adenosine deaminase enzyme is to eliminate a molecule called deoxyadenosine, which is generated when DNA is broken down. Adenosine deaminase converts deoxyadenosine, which can be toxic to lymphocytes, to another molecule called deoxyinosine that is not harmful.

Mutations in the ADA gene reduce or eliminate the activity of adenosine deaminase and allow the buildup of deoxyadenosine to levels that are toxic to lymphocytes.

Immature lymphocytes in the thymus are particularly vulnerable to a toxic buildup of deoxyadenosine. These cells die before they can mature to help fight infection. The loss of infection-fighting cells results in the signs and symptoms of SCID.

Management Bone marrow transplantation can be helpful Injections of ADA conjugate reduce the number and severity of infections Gene therapy where a retroviral vector carrying a normal copy of ADA gene is allowed to infect the patient borne marrow cells the ADA gene function within some of these genes and the pts immune status improved

Class II MHC Molecule Failure impairs the function of CD4 helper T cell because they can only recognize antigens presented by the class ll molecule. consequently both cell mediated and T dependent are impaired. SCID patient is treated with -Bone marrow transplantation. -Gene therapy

B. WISKOTT-ALDRICH SYNDROME Recurrent pyogenic infection, eczema and bleeding caused by thrombocytopenia Appears during 1st year of life it is x- linked disease Important defect is failure to mount an IgM response to the capsular polysaccharide of bacteria such as pneumococci The defect is in T-cells to which fail to provide help to B- cells. The mutant gene encodes a protein involved in actin filament assembly. Bone marrow transplant may be helpful

C. ATAXIA- TALANGIECTASIA is a rare inherited disorder affects the nervous system, immune system, and other body systems. characterized by progressive difficulty with coordinating movements (ataxia) beginning in early childhood before age 5. Affected children develop difficulty walking,

muscle twitches (myoclonus), and problems with balance and hand coordination, involuntary jerking movements (chorea), muscle twitches (myoclonus), and disturbances in nerve function (neuropathy). slurred speech and trouble moving their eyes to look side-to-side (oculomotor apraxia).

Disease caused by mutation in the genes that encode DNA repair enzymes. Treatment designed to correct immunodeficiency has not been successful

COMPLEMENT DEFFICIENCY

A. HEREDITARY ANGIO EDEMA Caused by a deficiency of C1 Inhibitor In the absent of Inhibitor C1 continuous to act on C4 to generate C4a and subsequently additional vasoactive components such as C3a and C5a this lead to capillary permeability and edema in several organs laryngeal edema can be fatal Steroid drugs can be useful

B. Recurrent infections Patients with deficiency in C1,C3,C5 have an increased susceptibility to bacterial infections. Those with reduced level of (C6,C7,C8) are prone to recurrent Neisseria gonorrhea & N. meningitides infections. Inherited deficiency of C1q, C2 and C4 increase risk of immune complex mediated disease by impairing the clearance of immune complexes from circulation .

Decay-accelerating factor (DAF) deficiency Causes Paroxysmal Nocturnal Hemoglobinuria is a rare disease Characterized by episodes of brownish urine (hemoglobinuria), esp. upon arising There is a deficiency of decay-accelerating factor (DAF) on the surface of blood cell precursors, leading to an increased activation of complement , hence haemolysis

Decay-accelerating factor (DAF, CD55), an intrinsic membrane glycoprotein of red cells, granulocytes, platelets and lymphocytes, DAF functions as a complement regulatory factor by inhibiting assembly and accelerating dissociation of C3 and C5 convertases of the classical and alternative pathways

There is a defect in the gene for the molecules that anchor DAF and other proteins to the cell membrane. No specific treatment. Give Iron for the anemia, and prednisone can help.

Phagocyte deficiencies A. Chronic granulomatous disease Patients are prone to opportunistic diseases Appears at 2yrs of age Is due to defect in the intracellular microbicidal activity of neutrophils as a result of lack of NADPH oxidase activity or similar enzymes

as a result no hydrogen peroxide or superoxide are produced ( i. e as a result no hydrogen peroxide or superoxide are produced ( i.e. no oxidative bust occurs) and the organism although ingested are not killed. treatment Aggressive treatment with antibiotic Gamma interferon reduce the frequency of recurrent infections

B . Chediak-higashi syndrome recurrence pyogenic infections caused by staphylococcus & streptococcus disorder that arises from a mutation of a lysosomal trafficking regulator protein,which leads to a decrease in phagocytosis

Diagnosis The diagnosis is confirmed by bone marrow smears that show "giant inclusion bodies" in the cells that develop into white blood cells (leukocyte precursor cells). There is no specific treatment for Chédiak–Higashi syndrome. Bone marrow transplants appear to have been successful in several patients. Infections are treated with antibiotics and abscesses are surgically drained when appropriate.

C. Job`s syndrome (hyper IgE syndrome) Job’s syndrome is a rare condition which affects both males and females with symptoms usually beginning in childhood. The most common features are eczema, increased susceptibility to infections and markedly raised levels of IgE

Patients with this syndrome have recurrent “cold” staphylococcus abscesses, eczema skeletal effects and high level of IgE Defect is the failure to produce gamma interferon by helper T- cells which reduces the ability of macrophages to kill bacteria this lead to an increase in Th2 cells and consequences a high IgE level

Job`s syndrome

Treatment of Hyper IgE Syndrome Therapy of HIES remains largely supportive. Antibiotic prophylaxis used against recurrent respiratory infections. skin care and prompt treatment of skin infections When the eczema is severe, topical moisturizing creams can help

SECONDARY IMMUNODEFICIENCIES. More common than primary. acquired from either iatrogenic cause or infection. Patients receiving immunosuppressive drugs for prevention of graft rejection or Rx of autoimmune diseases. Can be from malnutrition Cancer

Pts present with recurrent infections caused by pyogenic bacteria B- CELL DEFICIENCY A COMMON VARIABLE HYPERGAMMAGLUBULINEMIA Pts present with recurrent infections caused by pyogenic bacteria The infection occur btn the age 15 and 35yrs the B- cells inability to synthesize IgG and other immunoglobulin is greatly reduced the cause is unknown but appears to be due to defective in T-cell signaling Intravenous gamma globulin given monthly reduce number of infection

B. Malnutrition Can reduce the supply of amino acid and thereby reduces the synthesis of IgG this predispose to infection by pyogenic bacteria

T-cell deficiency A. Acquired immunodeficiency syndrome reduces helper T cells number by retrovirus infection which infect and kill cells bearing the CD4 protein as a surface receptor

Complement deficiency A. Liver failure caused alcoholic or by chronic Hepatitis B or C can reduce the synthesis of complement protein by the liver to level that pyogenic infection can occur B Malnutrition severe malnutrition can reduce supply of amino acids and thereby reduce the synthesis of complement protein by the liver this predispose to infection

Phagocyte deficiency A. Neutropenia patients present with severe infection caused by pyogenic bacteria such as S. aureus, S. pneumonia and enteric gram negative rods neutrophils count below 500/µL predispose to these infection Common cause of neutropenia include cytotoxic drugs Ciprofloxacin is used to try to prevent infections

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