Combined Immunodeficiency A talk on the Pathogenesis & Therapies For CID <br />Disorders of Blood & Immune System<br />Lec...
CID<br /><ul><li>Lack of necessary immunity in the body
Defects in production OR maturation of T cells &/or B cells of acquired immunity
Susceptible to recurrent infections; esp. by Candida albicans, Steph. aureus, etc.
Sterile-isolation, Immune Therapy, BM Therapy, Gene Therapy, Antibiotics.</li></li></ul><li>CID - Pathogenesis<br /><ul><l...
Mutagenic defects
 Metabolic deficiencies
Protein Defects (DNA-binding Proteins)
Eight types of immunodeficiencys
Six out of 8 – genetic defects
The rest – metabolic deficiencies</li></ul>T cell<br />(www.lbl.gov/Publications/Currents/Archive/Oct-03-2003.html#head0)<...
Mutagenic CID<br /><ul><li>Due to mutations in genes
Autosomal Recessive
ZAP-70 Deficiency
Bare Lymphocyte Syndrome
JAK3 Deficiency
Omenn’s Syndrome
X-linked
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Combined Immunodeficiency

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Combined Immunodeficiency and/or Severe Combined Immunodeficiency

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Combined Immunodeficiency

  1. 1. Combined Immunodeficiency A talk on the Pathogenesis & Therapies For CID <br />Disorders of Blood & Immune System<br />Lecturer: Dr. Sin Yoke Min<br />Compiled and Presented by<br />Su Htwe Cho, BBSF1 0707A<br />
  2. 2. CID<br /><ul><li>Lack of necessary immunity in the body
  3. 3. Defects in production OR maturation of T cells &/or B cells of acquired immunity
  4. 4. Susceptible to recurrent infections; esp. by Candida albicans, Steph. aureus, etc.
  5. 5. Sterile-isolation, Immune Therapy, BM Therapy, Gene Therapy, Antibiotics.</li></li></ul><li>CID - Pathogenesis<br /><ul><li>Directly related to production of T and B cells of the Adaptive Immunity
  6. 6. Mutagenic defects
  7. 7. Metabolic deficiencies
  8. 8. Protein Defects (DNA-binding Proteins)
  9. 9. Eight types of immunodeficiencys
  10. 10. Six out of 8 – genetic defects
  11. 11. The rest – metabolic deficiencies</li></ul>T cell<br />(www.lbl.gov/Publications/Currents/Archive/Oct-03-2003.html#head0)<br />Regulation of B Cell Development (2007)<br />(www.tmd.ac.jp/med/mbch/projects_English.htm)<br />
  12. 12.
  13. 13. Mutagenic CID<br /><ul><li>Due to mutations in genes
  14. 14. Autosomal Recessive
  15. 15. ZAP-70 Deficiency
  16. 16. Bare Lymphocyte Syndrome
  17. 17. JAK3 Deficiency
  18. 18. Omenn’s Syndrome
  19. 19. X-linked
  20. 20. XSCID
  21. 21. X-linked Lymphoproliferative Disease
  22. 22. Wiskott-Aldrich Syndrome</li></ul>Cavazzana & Fisher (2007)<br />Pike-Overzet et al. (2007)<br />
  23. 23. Enzyme Deficient CID<br />Due to the deficiency of enzymes <br />Deficient enzymes cause accumulation of toxic metabolic intermediates that blocks immune cell maturation<br />Two types of enzyme deficiencies are : <br />ADA (Adenosine Deaminase) deficiency<br />PNP (Purine Nucleoside Phosphorylase) deficiency<br />
  24. 24. Mutagenic CIDs -Autosomal Recessive<br />X-linked SCID<br />Genes encoding portions (gamma chains) of cytokine receptors of Interleukins IL2, IL4, IL7, IL9, IL15, IL21.<br />Interleukin Receptor protein is encoded on X chromosome<br />Mutations in X-chromosome =&gt; XSCID<br />Males Descendents Affected, Females Descendents Carriers unless both parents carry mutagenic genes<br />IL2R - Lymphocyte proliferation signaling absent<br />IL4R - B cell class-switch defected<br />IL7R - Loss of antiapoptotic signal, Loss of T cell selection in Thymus <br />IL15R - Ablation of of NK cell Development<br />Infectious mononucleosis, X-linked lymphoproliferative disease could happen secondary to XSCID<br />
  25. 25. Mutagenic CIDs – X Linked<br />Wiskott-Aldrich Syndrome <br />Absence of isohemagglutins & alteration of <br /> cell membrane glycoprotein sialophorin (CD43)<br />Absence or Low IgM, Elevated IgA, Normal IgG<br />Compromised T & B cell fuctions<br />Fail to produce antibodies to polysaccharide antigens<br />Smaller Lymphocytes with fewer microvilli<br />Eczema, Bloody Diarrhea, Thrombocytopenia<br />JAK3 Deficiency<br />Cytokine receptors using gamma chains associate with JAK3 tyrosine kinase & major cytokine receptors transducing subunits bind to JAK1 <br />Expression of JAK3 gene is important for lymphoid development and function<br />Defects in JAK3 gene could lead to defective production of lymphocytes<br />This 1-year-old boy was noted to have eczema and petechiae<br />His history was significant for a subdural hematoma for which trauma <br />Was denied; at that time the platelet count was 212,000. His diagnosis of <br />Wiskott-Aldrich Syndrome (WAS) was confirmed by the detection of a <br />missense mutation (Phe 128 Ser).<br />    Fig.:  The organization of the Jak homology (JH) domains of the Jak3 protein (Notarangelo and Vihinen 1999).<br />
  26. 26. Mutagenic CIDs -Autosomal Recessive<br /><ul><li>Bare Lymphocyte Syndrome
  27. 27. Severe defects in both cellular and humoral immune responses
  28. 28. MHC Class I deficiency
  29. 29. MHC class I molecules not expressed on lymphocyte membranes
  30. 30. MHC Class II deficiency
  31. 31. Lymphocytes and monocytes</li></ul>fail to express class II MHC antigens<br /><ul><li>Agammaglobulinemia, </li></ul>diminshed cell-mediated immunity<br />http://pathmicro.med.sc.edu/bowers/ant-pres.htm<br />
  32. 32. Mutagenic CIDs -Autosomal Recessive<br /><ul><li>ZAP70 Deficiency
  33. 33. Absence of CD8+T cells
  34. 34. Abundant CD3+/CD4+T lymphocytes </li></ul> that don’t respond to TCR mediated <br /> stimuli, in peripheral blood<br /><ul><li>ZAP70 is a non-src family protein </li></ul> tyrosine kinase necessary in T cell <br /> signaling<br /><ul><li>ZAP70 needed for physiologic </li></ul> development & function of T cells<br /><ul><li>Marked by CD8 lymphocytopenia</li></ul>www.bio.davidson.edu/courses/Immunology/Students/spring2006/Scognamiglio/Fig3.GIF<br />www.bio.davidson.edu/courses/Immunology/Students/spring2006/Scognamiglio/Fig4.GIF<br />
  35. 35. Omenn’s Syndrome<br />Immunoglobulin & TCR recombination genes : RAG (Recombination activation gene) 1 & 2 mutations <br />Artemis Defect (VDJ rearrangement)<br />Th2 mediated condition; Depleted B cells<br />Elevated Serum IgE, Circulating and tissue-infiltrating <br /> T lymphocytes increased<br />Lymph node architecture grossly abnormal<br />Characterized by protracted diarrhea, hepatosplenomegaly, hypereosinophilia<br />Mutagenic CIDs -Autosomal Recessive<br /> www.itb.cnr.it/flex/images/D.f910a9dcfd7a58b35d44/infant_omenn_syndrome.jpg<br />
  36. 36. Enzyme Deficient CIDs<br />Adenosine Deaminase (ADA) Deficiency <br />Abnormal ADA or lack of ADA couldn’t <br /> bind to deoxyadenosine<br />Deoxy-adenosine levels rise up<br />Kill T and B cells &gt; No Adaptive Immunity <br />PNP deficiency<br />Purine Nucleoside Phosphorylase Deficiency<br />PNP &gt;&gt; involved in purine degradation<br />T & B cell development <br />Underdeveloped thymus in infants<br />Autosomal Recessive<br />wikipedia/commons/c/c6/Adenosine_deaminase_1VFL.png<br />http://necat.chem.cornell.edu/Structures2/Struct_Pic2/3GGS.jpg<br />ADA Deficiency (2010)<br />
  37. 37. Treatments<br /><ul><li>Bone Marrow Transplantation OR Hemopoietic Stem Cell Transplantation
  38. 38. Somatic Gene Therapy (Retrovirus gene therapy)
  39. 39. Passive Administration &/or transfusion of Deficient Antibodies
  40. 40. Introduction of Deficient Enzymes (Adenosine Deaminase, Purine Nucleoside Phosphatase)</li></ul>Plus, Antibiotics for the recurrent infections!<br />
  41. 41. Treatments <br /><ul><li>Various Experiments – Murine Models</li></ul>Introduction of Foreign T & B cells<br />Steps : <br />Radiation Therapy – kill all lymphoid cells <br />Introduction of Immune Cells into <br /> Peripheral blood (transfusion)<br />(3) No graft Vs. Host disease &lt;- No Immunity<br /><ul><li>Result – Successful expression of </li></ul> immune responses after Therapy<br />Currently a treatment option<br />
  42. 42. Treatments<br />Bone Marrow & Xenogenic<br />Transplantation<br />Steps:<br /> (1) Radiation Therapy<br /> (2) Bone Marrow & Thymus <br /> Fragments Introduced<br /> (3) No Rejection of Foreign <br /> Tissue/ Stem Cells<br /><ul><li>Result – Successful !</li></ul>Currently a treatment option<br />
  43. 43. Somatic Gene Therapy <br />Steps:<br /> (1) Transfection of stem cells <br /> with normal copy of the genes<br /> (2) Reinfusion of transfected<br /> cells into circulation<br /><ul><li>Result - Successful expression of immune responses after the Therapy</li></ul>A Potential treatment option<br />Treatments<br />http://openlearn.open.ac.uk/file.php/2430/formats/SK195_5_rss.xml<br />
  44. 44. References<br /><ul><li>Jeff M. Milunsky, Stephen I. Pelton; Clinical and Genetic Perspectives in Primary Immunodeficiency Disorders.
  45. 45. A. Villa, Cristina Sobacchi, Francesca Rucci, Veronica Marella, Jessica Galleani (2009); Genetics of Primary Immunodeficiency's; Institute of Biomedical Technologies, National Research Council
  46. 46. 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</li></ul>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.<br />Adenosine Deaminase Deficiency (2010); Genetics Sci Learning Center; University of Utah. &lt;http://learn.genetics.utah.edu/content/disorders/whataregd/ada/&gt;<br />Regulation of B cell development (2006); &lt;www.tmd.ac.jp/med/mbch/projects_English.htm&gt;<br />Notarangelo LD, Vihinen M.  1999.  JAK3base: Mutation registry for autosomal recessive severe combined JAK3 deficiency.  &lt;http://www.uta.fi/imt/bioinfo/JAK3base&gt; <br /><ul><li>ZAP 70;<ww.bio.davidson.edu/courses/Immunology/Students/spring2006/Scognamiglio/ZAP.htm>
  47. 47. The Case of the Missing Enzyme: <ww.microvet.arizona.edu/Courses/MIC419/Secure/CaseNoIg/CaseNoIg.html>
  48. 48. JAK3: <www.bio.davidson.edu/COURSES/Immunology/Students/spring2000/haines/jak3.html>
  49. 49. Chapter 21 Immunodeficiency Diseases; The Immune System in Health and Disease – Part IV.
  50. 50. Chapter 7 Organization of Expression of Immunoglobulin Genes; Part II - Generation of B-Cell & T-Cell Responses.
  51. 51. Chapter 9 Failures of the Body’s Defenses; Inherited Immunodeficiency Diseases.
  52. 52. Atlas of Immunology; Immunodeficiences: Congenital & Acquired.
  53. 53. Chapter 3 Antigen Recognition by T Lymphocytes; T-cell Receptor Diversity & Antigen Processing and Presentation.</li></li></ul><li>Any Questions?<br />
  54. 54. Thanks<br />
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