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EM Semmelweis University November 28/ 2016 Increased susceptibility to infections and tumors Primer immune defficiencies IgG defficiency XLA Hyper IgM syndrome SCID: severe combined immunodeficiency disease Lack of T lymphocytes and adaptive immunity, (result of several gene mutations) Chains of cytokine receptor and signalling molecules are coded by 3 genes, 5 genes are required for development of antigene receptor (adenosine deaminase, purine salvage pathway, phosphatase – CD45). In human SCID developes as a result of complete deficiency of T cell antigene receptor/CD3 complex CD3ε chain. David Phillip Vetter (1971 – 1984) a texan (USA) boy suffered from SCID. Majority of his life was spent in a spacesuit like dress providing sterile environment in Children Hospital/ in Houston. He was known in the media as „the boy in the plastic bubble” A bone marrow transplant from his sister resulted his death when he was 13 yrs old. SCID: severe combined immunodeficiency disease J Clin Invest. 2004;114(10):1409–1411. DiGeorge syndrome (DGS, congeniális thymus hypoplasia, III.-IV. pharyngeal arch syndrome) 22q11.2 deletion syndrome Prevalence ~ 1:4000 It was described by the pediatric-endocrinologist Angelo DiGeorge in 1968. There is a wide range of symptomes. Chief symptomes are such inborn deficiencies like • congenital heart failure, • closing palate disorders, • deffects of velo-pharyngeal closing, • learning ability disorder, • face deformities, • recurrent infections X-chrs linked agammaglobulinemia (XLA, Bruton type agammaglobulinemia, Bruton syndrome) Deficiency of B cells and IgG in peripherial blood • Pathogenesis: impaired differeciation and growth of pre-B lymphocytes • Genetics: XR, males • Clinical characteristics: recurrent bacterial infections, lack of Ab responses in vaccination • Treatment: pooled gamma globulin products Smallpox vacciation 22 months old boy - XLA linked vaccinia necrosum. http://www.rightdiagnosis.com/phil/html/smallpox/3328.html Hyper-IgM Syndrome (Ig immunodeficiency with increased levels of IgM) Patients are unable to transform IgM to IgG, IgA and IgE. Therefore there are decreased IgG and IgA levels with normal or increased IgM levels. • Pathogenesis: lack of T cell CD40L. CD40L does not bound to CD40 on the B cells there is no B cell stimulation to take place class switch. • • Genetics：XR, male (frequently), AR (rare) Clinacal characteristics：recurrent pyogenic infections, increased IgM levels, decreased IgA and IgG Selective IgA deficiency (SIGAD) (frequent) • • • Immunological characteristics: deficiency of serum IgA <50mg/L Pathogenesis: problem with the terminal differenciation of B cells Clinical characteristics: recurrent infections of respiratory, intestine and urogenital system. • Treatments: in some cases the IgA synthesis is spontaneously recovered as a result of breast feeding. Chronic granulomatosis (CGD) Immunology Pathogenesis： decreased number and impaired function of phagocytes NADH/NADPH oxidase deficiency in neutrophils Decreased bactericid ability based on oxygen is a diverse genetic deficiency where the synthesis of reactive oxygen radicals for killing intracellular pathogens is decreased in immunecompetent cells. (most frequently the sureoxide synthesis is disturbed). The deficiency leads to formation of granulomas in different organs. Prevalence in USA 1:200,000. Chronic Granulomatous Disease-Causes-Symptoms-DiagnosisTreatment-Complications | Medindia http://www.medindia.net/patients/patientinfo/chronicgranulomatous-disease.htm#ixzz1fa7vXQlO Non-specific immunodeficiencies Deficiencies of complement komponents: • • • • genetic disorders of complement system involvement of regulatory proteins (e.g. herediter angioedema, C1INH deficiency) vasodilatation, increased vascular permeability (capillaries) edemas of skin and mucous membranes Wiskott–Aldrich syndrome (WAS), XR Eczema, thrombocytopenia, immune deficiency, blood in stool (as a result of thrombocytopenia). Described by Aldrich (1954). Secondary immundeficiencies • Tumors - especially disorders of bone marrow and periferial blood (leukemia, lymphoma, multiple myeloma) • Iatrogenic factors (immunosuppressive drugs, DMARDs, chemotherapy, radiotherapy) • • • • Malnutrition Ageing Some chronic infections Aquired immunodeficiency syndrome (AIDS) DMARDs - Disease-modifying antirheumatic drugs AIDS AIDS Facialis sarcoidosis Pneumocystis carinii cysts AIDS HIV/AIDS statistics - 2006 HIV Membrane: from the membrane of the host three glycoproteins: gp160, gp120 and gp41 gp41 is a transmembrane protein, gp120 is an ectoprotein associated to the membrane non-covalently HIV - cycle internalization Main target cell: CD4+T sejt human HeLa cell ahumán HeLa cells transfected by CD4 antigen No infection Incected HIV internalization into macrophages Complications of AIDS (opportunist pathogens) Kaposi sarcoma