Combined Immunodeficiency

Combined Immunodeficiency A talk on the Pathogenesis & Therapies For CID
Disorders of Blood & Immune System
Lecturer: Dr. Sin Yoke Min
Compiled and Presented by
Su Htwe Cho, BBSF1 0707A

CID
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.

CID - Pathogenesis
Directly related to production of T and B cells of the Adaptive Immunity
Mutagenic defects
Metabolic deficiencies
Protein Defects (DNA-binding Proteins)
Eight types of immunodeficiencys
Six out of 8 – genetic defects
The rest – metabolic deficiencies
T cell
(www.lbl.gov/Publications/Currents/Archive/Oct-03-2003.html#head0)
Regulation of B Cell Development (2007)
(www.tmd.ac.jp/med/mbch/projects_English.htm)

Mutagenic CID
Due to mutations in genes
Autosomal Recessive
ZAP-70 Deficiency
Bare Lymphocyte Syndrome
JAK3 Deficiency
Omenn’s Syndrome
X-linked
XSCID
X-linked Lymphoproliferative Disease
Wiskott-Aldrich Syndrome
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).

Bare Lymphocyte Syndrome
Severe defects in both cellular and humoral immune responses
MHC Class I deficiency
MHC class I molecules not expressed on lymphocyte membranes
MHC Class II deficiency
Lymphocytes and monocytes
fail to express class II MHC antigens
Agammaglobulinemia,
diminshed cell-mediated immunity
http://pathmicro.med.sc.edu/bowers/ant-pres.htm

ZAP70 Deficiency
Absence of CD8+T cells
Abundant CD3+/CD4+T lymphocytes
that don’t respond to TCR mediated
stimuli, in peripheral blood
ZAP70 is a non-src family protein
tyrosine kinase necessary in T cell
signaling
ZAP70 needed for physiologic
development & function of T cells
Marked by CD8 lymphocytopenia
www.bio.davidson.edu/courses/Immunology/Students/spring2006/Scognamiglio/Fig3.GIF
www.bio.davidson.edu/courses/Immunology/Students/spring2006/Scognamiglio/Fig4.GIF

Omenn’s Syndrome
Immunoglobulin & TCR recombination genes : RAG (Recombination activation gene) 1 & 2 mutations
Artemis Defect (VDJ rearrangement)
Th2 mediated condition; Depleted B cells
Elevated Serum IgE, Circulating and tissue-infiltrating
T lymphocytes increased
Lymph node architecture grossly abnormal
Characterized by protracted diarrhea, hepatosplenomegaly, hypereosinophilia
www.itb.cnr.it/flex/images/D.f910a9dcfd7a58b35d44/infant_omenn_syndrome.jpg

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)

Treatments
Bone Marrow Transplantation OR Hemopoietic Stem Cell Transplantation
Somatic Gene Therapy (Retrovirus gene therapy)
Passive Administration &/or transfusion of Deficient Antibodies
Introduction of Deficient Enzymes (Adenosine Deaminase, Purine Nucleoside Phosphatase)
Plus, Antibiotics for the recurrent infections!

Treatments
Various Experiments – Murine Models
Introduction of Foreign T & B cells
Steps :
Radiation Therapy – kill all lymphoid cells
Introduction of Immune Cells into
Peripheral blood (transfusion)
(3) No graft Vs. Host disease <- No Immunity
Result – Successful expression of
immune responses after Therapy
Currently a treatment option

Treatments
Bone Marrow & Xenogenic
Transplantation
Steps:
(1) Radiation Therapy
(2) Bone Marrow & Thymus
Fragments Introduced
(3) No Rejection of Foreign
Tissue/ Stem Cells
Result – Successful !
Currently a treatment option

Somatic Gene Therapy
Steps:
(1) Transfection of stem cells
with normal copy of the genes
(2) Reinfusion of transfected
cells into circulation
Result - Successful expression of immune responses after the Therapy
A Potential treatment option
Treatments
http://openlearn.open.ac.uk/file.php/2430/formats/SK195_5_rss.xml

References
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>
ZAP 70;
The Case of the Missing Enzyme:
JAK3:
Chapter 21 Immunodeficiency Diseases; The Immune System in Health and Disease – Part IV.
Chapter 7 Organization of Expression of Immunoglobulin Genes; Part II - Generation of B-Cell & T-Cell Responses.
Chapter 9 Failures of the Body’s Defenses; Inherited Immunodeficiency Diseases.
Atlas of Immunology; Immunodeficiences: Congenital & Acquired.
Chapter 3 Antigen Recognition by T Lymphocytes; T-cell Receptor Diversity & Antigen Processing and Presentation.

Any Questions?

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Combined Immunodeficiency

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