Cavazzana & Fisher (2007) Pike-Overzet et al. (2007)
Enzyme Deficient CID Due to the deficiency of enzymes Deficient enzymes cause accumulation of toxic metabolic intermediates that blocks immune cell maturation Two types of enzyme deficiencies are : ADA (Adenosine Deaminase) deficiency PNP (Purine Nucleoside Phosphorylase) deficiency
Mutagenic CIDs -Autosomal Recessive X-linked SCID Genes encoding portions (gamma chains) of cytokine receptors of Interleukins IL2, IL4, IL7, IL9, IL15, IL21. Interleukin Receptor protein is encoded on X chromosome Mutations in X-chromosome => XSCID Males Descendents Affected, Females Descendents Carriers unless both parents carry mutagenic genes IL2R - Lymphocyte proliferation signaling absent IL4R - B cell class-switch defected IL7R - Loss of antiapoptotic signal, Loss of T cell selection in Thymus IL15R - Ablation of of NK cell Development Infectious mononucleosis, X-linked lymphoproliferative disease could happen secondary to XSCID
Mutagenic CIDs – X Linked Wiskott-Aldrich Syndrome Absence of isohemagglutins & alteration of cell membrane glycoprotein sialophorin (CD43) Absence or Low IgM, Elevated IgA, Normal IgG Compromised T & B cell fuctions Fail to produce antibodies to polysaccharide antigens Smaller Lymphocytes with fewer microvilli Eczema, Bloody Diarrhea, Thrombocytopenia JAK3 Deficiency Cytokine receptors using gamma chains associate with JAK3 tyrosine kinase & major cytokine receptors transducing subunits bind to JAK1 Expression of JAK3 gene is important for lymphoid development and function Defects in JAK3 gene could lead to defective production of lymphocytes This 1-year-old boy was noted to have eczema and petechiae His history was significant for a subdural hematoma for which trauma Was denied; at that time the platelet count was 212,000. His diagnosis of Wiskott-Aldrich Syndrome (WAS) was confirmed by the detection of a missense mutation (Phe 128 Ser). Fig.: The organization of the Jak homology (JH) domains of the Jak3 protein (Notarangelo and Vihinen 1999).
Enzyme Deficient CIDs Adenosine Deaminase (ADA) Deficiency Abnormal ADA or lack of ADA couldn’t bind to deoxyadenosine Deoxy-adenosine levels rise up Kill T and B cells > No Adaptive Immunity PNP deficiency Purine Nucleoside Phosphorylase Deficiency PNP >> involved in purine degradation T & B cell development Underdeveloped thymus in infants Autosomal Recessive wikipedia/commons/c/c6/Adenosine_deaminase_1VFL.png http://necat.chem.cornell.edu/Structures2/Struct_Pic2/3GGS.jpg ADA Deficiency (2010)
Jeff M. Milunsky, Stephen I. Pelton; Clinical and Genetic Perspectives in Primary Immunodeficiency Disorders.
A. Villa, Cristina Sobacchi, Francesca Rucci, Veronica Marella, Jessica Galleani (2009); Genetics of Primary Immunodeficiency's; Institute of Biomedical Technologies, National Research Council
Marina Cavazzana-Calvo and Alain Fischer (Jun 2007); Gene therapy for severe combined immunodeficiency: are we there yet? ; J. Clin. Invest. 117:6 doi:10.1172/JCI30953
Karin Pike-Overzet, Mirjam van der Burg, Gerard Wagemaker, Jacques JM van Dongen and Frank JT Staal (2007); New Insights and Unresolved Issues Regarding Insertional Mutagenesis in X-linked SCID Gene Therapy; Molecular Therapy; 15 11, 1910–1916. doi:10.1038/sj.mt.6300297. Adenosine Deaminase Deficiency (2010); Genetics Sci Learning Center; University of Utah. <http://learn.genetics.utah.edu/content/disorders/whataregd/ada/> Regulation of B cell development (2006); <www.tmd.ac.jp/med/mbch/projects_English.htm> Notarangelo LD, Vihinen M. 1999. JAK3base: Mutation registry for autosomal recessive severe combined JAK3 deficiency. <http://www.uta.fi/imt/bioinfo/JAK3base>