"Antibody Deficiency Syndromes."

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  1. Dra_Tavarez

    Dra_Tavarez Young Member

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    Development of antibody-mediated immunity
    Initially mature B lymphocytes independently of antigen. Since bone marrow precursor cells undergo various stages of maturation and differentiation. The immature B cell development, to the stage at which expresses surface IgM, depending on the normal activity of specific tyrosine kinase (Btk).
    The later stage of differentiation, until the formation of plasma cells capable of secreting antibodies depends on the presence of antigen and the interaction with T lymphocytes (helper). CD40 is a membrane antigen of B cells that binds to the CD40 ligand (CD40L) on activated T lymphocytes. The interaction between CD40 and CD40L is essential in the final differentiation of B lymphocytes
    Immunoglobulin levels gradually increased after birth, the IgG is the only way to cross the placenta. IgG synthesis against protein antigens occurs before the antipolysaccharide IgG, which is observed after two years of life.
    Antibody-mediated immunity
    The antibodies bind to infective organisms and facilitating phagocytosis (opsonization) by polymorphonuclear macrophages. The IgM and IgG are able to activate complement by the classical pathway. Antibody-mediated immunity is important in eliminating extracellular pathogens such as S. aureus, H. influenzae, S. pneumoniae and N. meningitidis and virus before entering the cell. Instead, experts added, cellular immunity is crucial for the elimination of intracellular pathogens.
    IgM is the first to appear in the ontogenetic scale and is the antibody produced in the primary immune response. IgG is the major immunoglobulin serum and extravascular, is the main secondary antibody responses. It immunoglobulin immunological memory and antibody that provides long-term protection against infection by viruses and pathogenic bacteria.
    The four known IgG subtypes IgG1, IgG2, IgG3 and IgG4 having concentrations of 60% to 65%, 20% to 25%, 5% to 10% and 3% to 6%, respectively. Antibodies against proteins are mainly represented in the IgG1 and IgG3 fraction, whereas polysaccharides are essentially directed against IgG2.
    IgA is the predominant antibody in mucosal secretions and exerts an important role to prevent the entry of microbial and heterologous antigens (food) to the body. Secretory IgA deficiency (IgA two molecules bonded secretory component) is extremely rare in the presence of normal serum IgA.
    Classification of antibody deficiencies
    The can be etiological classification (genetic, secondary or temporary) or phenotypic depending on immunoglobulin absent. Some of the abnormalities are an expression of a genetic mutation point. Also, certain similar immune phenotypes can result from different molecular alterations. Therefore, the primary antibody deficiencies syndromes are considered and no individual pathologies.
    Clinical manifestations of antibody deficiencies
    Recurrent infections represent the essential clinical manifestation. Arise, in typical form, when maternal IgG disappears, between 5 and 7 months of life. The infections are usually more severe and often lead to serious complications. Some specific infections suggest specific antibody deficiency. For example, children with X-linked agammaglobulinemia (XLA) may develop fatal enterovirus meningoencephalitis. Similarly, intercurrent infection by Giardia lamblia requires considering IgA deficiency.
    Thrombocytopenia and neutropenia are common infectious clinical manifestations in antibody deficiencies. The absence of secondary lymphoid tissue (tonsils, adenoids) suggests the most severe form of antibody deficiency, the XLA.
    However, the clinical expression may be highly variable in other situations and patients may be asymptomatic. Common variable immunodeficiency can be diagnosed at any time of life.
    Overall rating of antibody-mediated immunity
    The diagnosis is based on studies to identify phenotypic abnormalities (concentration of immunoglobulins and IgG subtypes, dosage of specific antibodies against proteins and polysaccharides, assessment of circulating B lymphocytes), genetic abnormalities and molecular alterations.
    Agammaglobulinemia
    It is the most serious situation antibody deficiency.
    IgG levels are usually below 200 mg% and IgM and IgA below 20 mg%. It is the only situation in which B lymphocytes are absent or very scarce. Cellular immunity is preserved.
    Between 4 and 6 months of age, the child begins to have pyogenic infections, mainly otitis, sinusitis and pneumonia and viral infections.
    The agammaglobulinemia is an example of immunologically defined phenotype. The most common form, the XLA is caused by mutations in the Btk gene on chromosome Xq 21.3-22. There autosomal forms which may result from abnormalities in the gene encoding the μ chain of IgM heavy chain.
    Btk mutations may accompany milder variants that arise in the later stages of life. XLA diagnosing Btk by mutation must be verified in men with less than 2% of B lymphocytes (CD19 +). The family history is important.
    HiperIgM syndrome
    In these patients is characteristic IgA and IgG deficiency with normal or increased IgM. The clinical phenotype attributable to lock in immunoglobulin class switching, is characterized by frequent pyogenic infections and gastrointestinal diseases, autoimmune pathologies recurrent neutropenia. Although the disease is typical of males, other modes of transmission also affect women.
    Almost all male patients with hiperIgM syndrome have a mutation in the CD40L gene on chromosome X. As discussed above, the interaction between CD40 and CD40L is critical to produce the change of class of immunoglobulins (IgM, IgG or IgA). Besides pyogenic infections, patients are more prone to infection by some intracellular microorganisms, such as P. carinii, central nervous system histoplasmosis and toxoplasmosis.
    Common variable immunodeficiency (CVID)
    It is a primary immunodeficiency hipogammaglobulinémica late onset after 18 months. There are two peaks of maximum occurrence: between the first and fifth year of life, and between 16 and 20 years. IgG concentration is low (at least two standard deviations below the mean for) and no reduction in the level of IgA and IgM. Isohemagglutinins undetected and the response to polysaccharide or protein vaccines is abnormal. Almost all patients have normal numbers of B cells There is also some alteration of cellular immunity.
    Clinically, patients are more prone to respiratory and gastrointestinal infections and increased incidence of autoimmune diseases (thrombocytopenia, hemolytic anemia, rheumatoid arthritis, lupus erythematosus, thyroiditis, vitiligo and primary biliary cirrhosis). Neoplasms frequency (lymphomas, stomach cancer) is greater in CVID. There is phenotypic overlap with other antibody immunodeficiencies, so the examination, family history and the presence of non-immune syndromes (Down syndrome, muscular dystrophy) can be oriented towards specific others. It must be considered that the alteration is secondary to drugs (antimalarials, captopril, carbamazepine, steroids, gold salts and penicillamine, etc.), infectious diseases (Epstein Barr virus, cytomegalovirus, congenital T. gondii infection) , lymphoproliferative diseases and systemic disorders (diarrhea, nephrosis).
    IgG in the presence of above 400 mg%, although the concentration is lower than expected based on age, not considered CVID. In the latter case should dosar level IgG subtypes and evaluate antigen-specific response.
    Most cases appears sporadically CVID although up to 25% of patients have a family can similarly affected or another deficiency (eg, selective IgA deficiency), which demonstrates the involvement of several genes and variable penetrance or expressivity of a given gene.
    Transient hypogammaglobulinemia of infancy
    There is a delay in the production of immunoglobulins that manifests the disappearance passive maternal immunity. The concentration of IgA and IgM is usually normal as the number of lymphocytes B. IgG level usually is normalized to the 2 or 3 years.
    IgM deficiency
    It is a rare entity that is seen in patients with recurrent infections, atopic dermatitis, lupus erythematosus and autoimmune hemolytic anemia.
    IgA deficiency
    The correct diagnosis is established after 4 years. Patients with complete absence of IgA are at greater risk of developing antibodies antiIgA to contact with any blood product containing this immunoglobulin.
    Selective IgA deficiency without clinical manifestations in some individuals, manifests with increased risk of respiratory infections, allergies, autoimmune enteropathy and disorders. Must be excluded or simultaneous appearance of IgG2 specific antibody deficiencies. Selective IgA deficiency is the most prevalent in almost everyone.
    IgG subclass deficiencies
    Can occur in isolation or in combination with other syndromes (ataxia telangiectasia or IgA deficiency). The severity of the clinical manifestations did not correlate with the level of deficit and have been described fully asymptomatic persons with absolute deficit IgG subclass. Besides the dosage of IgG subtypes, in affected patients must be studied production capacity of antibodies to protein antigens and polysaccharides.
    IgG1 deficiency is almost invariably associated with low total IgG level and representing 60% to 70% of it.
    IgG2 deficiencies are a heterogeneous group of anomalies of varying severity. It can cause recurrent infections in the ears, sinuses and lungs. Furthermore, the main fraction is IgG2 antibodies against polysaccharides.
    Most IgG3 deficiencies are moderate and rarely associated with defined clinical pathology. Finally, add the authors, many healthy infants and children have low or absent levels of IgG4.
    Specific antibody deficiency with normal immunoglobulins
    The alteration is established to evaluate the production of antibodies after pneumococcal vaccination, only children over two years of life. Some deficiencies are transient.
    Relationship between different forms of antibody deficiencies
    IgA deficiency and CVID can occur in multiple members of a family. With the passage of time can vary the phenotype, such as selective IgA deficiency can evolve CVID.
     

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