Immunodeficiency diseases
It is the absence or failure of normal function of one or more elements of the immune system.Primary Secondary , immunodeficiency is a result of a known condition.Primary IDPrimary Ab deficiency 1. X-linked agammaglobulinemia( Brutons҆ disease) Affect boys.Failure of B cell maturation, no development beyond pre-B cell stage in the bone marrow. Caused by mutation in the gene encoding of Brutons҆ tyrosin kinase (Btk) which is required for signal transduction from Pre-B cells receptor (pre BCR) for the differentiation of these cells.Low or undetectable serum Ig, reduced or absent B cells in peripheral blood & lymphoid tissues, no germinal centers in lymph nodes & no plasma cells in tissues.Function of T cells are normal, there may be reduced number of activated T cells due to reduced Ag presentation caused by lack of B cells. Symptoms appear after 6 months of age, after the weaning of maternal Abs. There is high incidence of otitis media, skin & respiratory infection caused mainly by H. influenzae, S. pneumoniae or S. aureus. Normal response to viral & fungal infections. Therapy : periodic injection of IV gamma globulin ( IVGG) containing large amount of IgG.
Pts have decrease serum IgG & IgA with normal or low IgM & a normal or low peripheral B cells. Affects both males & females . Cause is not clear, may be due to an inability of B cells to proliferate in response to Ags or normal proliferation without secretion of IgM or secretion of IgM without class switching due to intrinsic B or T cell abnormality.
Onset may occur at any age . Pts suffer from recurrent RTI, GIT with pyogenic bacteria. Autoimmune disease such as hemolytic anemia, thrombocytopenia & SLE which are associated with autoantibodies. Pts may have disorders of cell-mediated immunity May develop carcinoma and lymphomas . Treatment is with IVGG in severe cases.
Boys & girls are affected equally. Is the most common ID disorder in the western world. Can present at any age, most patients are presented as adults. Very low level of IgA with normal IgM & IgG. Cause is unknown, may occur transiently or as an adverse reaction to certain drugs. Defect in isotype switching of B cells into IgA production. Patients suffer from respiratory tract , gastrointestinal & urogenital infections.
Increase incidence of autoimmune disease, especially SLE, RA & celiac disease.May be entirely asymptomatic.Treatment :Wide – spectrum antibiotics.IgA injection is not useful because it does not get to the local secretory area where IgA is normally the protective Ab.Prognosis is good.
These boys have very low level of IgG, IgA, IgE with normal to high level of IgM. Mutation in the CD40L gene lead to failure of CD40 ligand expression on T cells which react with CD40 on B cells to trigger switching from IgM to IgG or IgA in Ag –stimulated B cells.Recruitment of B cells into follicle does not occur resulting in a lack of germinal center formation.The children have partial block in neutrophil differentiation & subtle T cell function.This explain their susceptibility to Pneumocytis carinii pneumonia. Pts present with recurrent RTI at 1-2 yrs of age.Treatment :Replacement of IGs.Bone marrow transplantation is now considered.
Occurs when the infant is slow to synthesize IgG as serum level of maternally acquired Abs continue to fall, the infant may become susceptible to recurrent pyogenic infections. It may take many months before spontaneous IgG synthesis begins. In most cases, the infant remains well & needs no specific therapy. Condition may resolve within 1- 2 yrs.
1.Congenital thymic aplasia ( DiGoerge syndrome) Condition is not hereditary. Mostly a result of deletion in chromosome 22q11 Is due to faulty development of the 3rd & 4th pharyngeal pouches which normally takes place during the 12 wks of gestation resulting in cardiac abnormalities, abnormal facies & failure of formation of thymus & parathyroids. Newborns present with hypocalcemia & congenital heart disease. Have either no or very few mature T cells in the periphery (blood, LN & spleen). The peripheral blood T cells are absent or greatly reduced in number. No cell-mediated immune response.
Abs level are usually normal but may be reduced in severely affected patients Children suffer from recurrent or chronic infection with viruses, bacteria, fungi & protozoa. Due to the absence of T cells and abnormal antibody response, these patients should not be immunized with live- attenuated vaccines. Treatment : Fetal thymus transplantation resulting in the appearance of T cell within a week.
An infection of skin & m.m with C.albicans. Have normal T cell response to m.o. other than candida. Normal Ab response to all m.o. including candida. Affect both males & females. Some evidence that it may be inherited.
Heterogeneous group of diseases in which both cell –mediated & Ab production are defective. rare, potentially fatal syndromeAre susceptible to any type of microbial infection. Infants are presented in the 1st few wks with recurrent infections, failure to thrive & lymphopenia. There are 12 genetic types
Mutation in the gene encoding the γ chain of IL-2 receptor located on X- chromosome . γ chain of IL-2 is common for the cytokines, IL-4, IL-7, IL-9 & IL-15 which are crucial for T development resulting in very low T-lymphocyte and NK- cell counts, but the B-lymphocyte count is high. so-called T-, B+, NK-phenotype. Despite the high number of B-lymphocytes, there is no B-lymphocyte function since the T-cells are not able to “help” the B-cells to function normallyleading to functional defect in CMI, Ab failure with abnormal NK cells
Small group of patients (5 % of SCID )Identical phenotype to X-linked type of SCID, cannot be distinguished clinically.Mutations is in the gene encoding for JAK3 tyrosin kinase , the intracellular molecule responsible for transmitting signals from the γ chain of IL -2 receptors.Thus, when T, B and NK-lymphocyte counts are done, infants with this type look very similar to those with X-linked SCID, i.e. they are T-, B+, NK-.
Another type of SCID is caused by mutations in a gene that encodes an enzyme called adenosine deaminase (ADA). ADA is essential for the metabolic function of a variety of body cells, but especially T-cells. The absence of this enzyme leads to an accumulation of toxic metabolic by-products within lymphocytes that cause the cells to die. ADA deficiency is the second most common cause of SCID, accounting for 15% of cases. Babies with this type of SCID have the lowest total lymphocyte counts of all, and T, B an NK-lymphocyte counts are all very low. This form of SCID is inherited as an autosomal recessive trait. Both boys and girls can be affected.
Treatment of SCID : Antimicrobial therapy. Immunization with live vaccine must be avoided. Blood transfusion should be avoided as it may result in GVHD unless blood is irradiated first. HLA-matched bone marrow transplantation is the treatment of choice for all kinds of SCID. Gene therapy .
Defect in neutrophil function :Neutropenia :Primary neutrpenia is rare.2nd ry to to chemotherapy for malignant diseases. Chronic granulomatous disease ( CGD ):Disorders due to failure to produce bactericidal oxygen radicals during resp. burst. The classic type is an X – linked recessive disorder & typically present in the first 2 months of life.Usual complications , regional lymphadenopathy, hepatosplenomegaly, hepatic abscess & osteomylitis.Affected organs show multiple abscesses caused by S.aureus & gram negative bacilli or fungi.Treatment : prophylactic antibiotics & INF gamma .
AIDS is the final stage in the progression of infection with HIV. Profound immunosuppression that lead to opportunistic infections, neoplasms & neurological manifestations. Causative agent are retroviruses HIV type 1 & type 2. HIV enter susceptible cell through binding of viral envelope gp(120) to CD4 molecule in addition to binding to a coreceptor ( CCR5 & CXCR4 ). Any cell bearing the CD4 is capable to be infected with HIV, typically these are helper T- cell but some B cells, macrophages , dendritic cells & glial cell of CNS also express CD4 even in low amount. The viral genome undergo reverse transcription forming proviral DNA. In dividing T cells , the proviral DNA enter the nucleus & integrate in the host genome, this causes either entry of virus into latent state or extensive viral budding with cell death.
The most striking effect of HIV is on CMI.HIV has intrinsically unstable epitops for ABs to bind thus making production of effective neutralizing Abs difficult.The fall in the absolute number of CD4 T cells makes the pt symptomatic entering the final phase of the disease ( AIDS).Polyclonal B – activation results in a rise of serum Igs conc. in 80 – 90 % of pts.Responses to new Ags are impaired due to dysfunction of APCs.Even in pts with wide –spread opportunistic infections, there may be no detectable specific Ab response.Autoimmunity & malignancies both (lymphoid & non lymphoid) reflects loss of immune regulation due to HIV.