Semmelweis University Immune deficiencies EM Semmelweis University November 28/ 2016

Increased susceptibility to infections and tumors Immune defficiencies 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 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

22 months old boy - XLA linked vaccinia necrosum. 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 decreased number and impaired function of phagocytes Pathogenesis： 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-Diagnosis-Treatment-Complications | Medindia http://www.medindia.net/patients/patientinfo/chronic-granulomatous-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

Pneumocystis carinii cysts 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 The establishment that the disease is caused by a virus and therefore the ability to produce antibodies against viral antigens led to the first tests for HIV, the ELIZA and Western blot tests. However, there is a 1 to 2 month time lag before antibodies are produced. This can be overcome by using a test that identifies viral RNA rather than antibodies produced against viral protein e.g PCR. The very fact that we can use an antibody test shows us that there is a good immune response and it is neutralizing antibody which gives hope for a vaccine. But the virus is not completely neutralized which argues that a vaccine may be difficult to develop. The virus goes underground within the cells and because it is a retrovirus, is prone to genetic drift. As it changes it overcomes the immune system. As we shall see retroviral vaccines pose special problems and HIV is more complicated than other retroviruses

Main target cell: CD4+T sejt ahumán HeLa cells transfected by HIV - cycle internalization Main target cell: CD4+T sejt ahumán HeLa cells transfected by CD4 antigen human HeLa cell Human HeLa cells are not infected by HIV because they do not have CD4 antigen. When CD4 gene was transfected into the HeLa cells, they became able to bind HIV and were infected. No infection Incected

HIV internalization into macrophages

(opportunist pathogens) Complications of AIDS (opportunist pathogens) Kaposi sarcoma