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Background on Zap70 SCID. Slides from Arthur Weiss GEMS Journal Club August 2012. Case Presentation. A 1 year old Hispanic female was referred to UCSF for the possibility of a bone marrow transplantation. She had a history of: recurrent pneumonias chronic gastroenteritis

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Background on zap70 scid

Background on Zap70 SCID

Slides from Arthur Weiss

GEMS Journal Club

August 2012


Background on zap70 scid

Case Presentation

A 1 year old Hispanic female was referred to UCSF for the

possibility of a bone marrow transplantation.

She had a history of:

recurrent pneumonias

chronic gastroenteritis

failure to thrive

oral/cutaneous candidiasis

history of disseminated varicella

Her parents were first cousins.

One of her three sibs (brother) died at age 9 months.

Physical Exam was unremarkable


Background on zap70 scid

Laboratory Evaluation

  • B cell number: Normal

  • Immunoglobulin levels: Decreased IgM, IgG and IgA

  • Abnormal lymphocyte phenotype:

  • CD3 76%; CD4 74%; CD8 0-2%

  • T cells are polyclonal

  • In vitro proliferation studies:

    • B cells proliferate normally to mitogens

    • CD4 T cells:

    • Fail to respond to PHA or anti-CD3 mAb

      • Positive proliferative response to IL-2

      • Positive proliferative response to PMA plus ionomycin


Background on zap70 scid

Severe Combined Immunodeficiency Syndrome

SCID

  • Primary Defect

    • - Absent T cell function

    • - Variable T cell counts (absent to elevated)

  • Associated Defects

    • - Decreased B cell responses (intrinsic or extrinsic)

    • - Variable B cell counts (often normal)


Background on zap70 scid

Multiple Molecular Causes of SCID

  • X-linked Common  chain (IL-2, IL-4, IL-7, IL-9,

  • and IL-15 receptors) - 50%

  • Jak 3 tyrosine kinase

  • IL-7 receptor alpha chain

  • Adenosine Deaminase (ADA)

  • Purine Nucleoside Phosphorylase (PNP)

  • Recombinase Activating Genes (Rag 1 and Rag 2)

  • CD3  and 

  • CD45 tyrosine phosphatase

  • Bare lymphocyte syndrome (absent MHC molecules)

  • ZAP-70 tyrosine kinase


Background on zap70 scid

Causes of severe T cell deficiency

Liston, Enders, Siggs

NRI, 2008


Background on zap70 scid

Unusual Phenotype of ZAP-70 Deficient SCID:

Absence of Peripheral CD8 T Cells

Chan, et al., Science, 1994


Background on zap70 scid

ZAP-70 Deficient CD4 T Cells Fail to Signal

in Response to TCR Stimulation

Chan, et al., Science, 1994

Patient Normal

TCR Stimulation

Western Blot

anti-phosphotyrosine




Background on zap70 scid

TCR Signaling is Initiated by Coordinated

Actions of Two Cytoplasmic Tyrosine Kinases:

Lck and ZAP-70

Wang, et al, CSHL, 2009



Background on zap70 scid

A Brief Introduction to T Cell

Development

T Cell Developmental Checkpoints

CD4

SP

DP

CD8

SP

CD4

DN

CD8

Pre-TCR Positive &

selection Negative

Selection


Background on zap70 scid

Complete T cell Developmental Arrest in

ZAP-70 Deficient Mice

Normal ZAP-70 KO

Thymocytes

CD4

Lymph node cells

CD4

CD8


Background on zap70 scid

Decreased Function of ZAP-70 Can

Lead to Autoimmunity


Background on zap70 scid

Spontaneous Development of Erosive Arthritis in SKG mice

Sakaguchi, et al, Nature, 2003

  • Incidental finding in Balb/c mouse colony

  • 100% penetrant, males and females affected

  • Onset at 2 months (joint swelling and hyperemia)

  • or following activation of the innate immune response

  • Interphalangeal joints -> symmetrical involvement including

  • wrist and ankle joints. Spares large joints and spine (except

  • base of tail) Destruction of joint space.

  • RF+, mediated by CD4 T cells


Background on zap70 scid

Hypomorphic Mutant Allele of ZAP-70 with Decreased

Catalytic Activity Associated with ANA Positive

Autoimmunity in Mice

Siggs, et al., Immunity, 2007


Thymocyte selection is dependent on signaling through the tcr

Signal strength

Thymocyte selection is dependent on signaling through the TCR

Signal strength = Affinity X TCR signaling intensity


Thymocyte selection is dependent on signaling through the tcr1

Signal strength

Thymocyte selection is dependent on signaling through the TCR

Decreasing

TCR Signaling

by ZAP-70

mutation

alters the

TCR repertoire

of thymocytes

surviving both

positive and

negative

selection

Signal strength = Affinity X TCR Signaling Intensity


Background on zap70 scid
Asymmetric effects on immunogenic and tolerogenic TCR signaling may account for autoimmunity with partial immunodeficiency

Liston, Enders, Siggs

NRI, 2008