Failure of host defence mechanisms & evolution of the immune
system – Robin van Bruggen
13-3
Severe combined immunodeficiency (SCID): Patients with defects in T cell development. They have
no T cell dependent antibody responses or cell mediate immune responses and are susceptible to a
broad range of infectious agents.
X-linked SCID (XSCID, bubble boy): Most frequent form of SCID caused by mutations in IL2RG (X
chromosome, mostly male) which encodes for IL-2 receptor common gamma chain. This common
gamma chain is required for IL-2/4/7/9/15/21 and so patients have defects in signalling of all these
cytokines. T cells and NK cells fail to develop → cannot help B cells anymore → abnormal B cell
function. They don’t make effective antibody responses.
➔ Female XSCID patients inactivate defective X chromosome in naive IgM B cells → B cell
development is affected by, but not wholly dependent on the common gamma chain.
Kinase Jak3 SCID: Inactivating mutation in Jak3, this physically associates with common gamma
chain and transduces signalling through the cytokine receptors. It has the same effects as XSCID.
Mice with mutations in IL-15 (or the alfa chain of the receptor) have no NK cells and have a defect in
the maintenance of memory CD8 T cells.
Humans with a deficiency of IL-7 receptor alfa chain have no T cells (but do have NK cells) → IL-7
signalling is essential for T cell development (and not NK).
➔ Mice with a deficiency in IL-7 receptor have no T cells & B cells → species specific role
cytokines.
Humans & mice with defective production IL-2 → impaired development FoxP3 Tregs →
autoimmunity.
13-4 – Defects in enzymes
There are also autosomal recessive variants of SCID due to defects in enzymes like adenosine
deaminase (ADA) deficiency & purine nucleotide phosphorylase (PNP) deficiency.
• ADA: Conversion adenosine/deoxyadenosine → inosine/deoxyinosine. Deficiency:
accumulation of deoxyadenosine (and precursor S-adenosylhomocysteine) which are toxic to
developing T and B cells.
• PNP: Conversion of inosine/guanosine to hypoxanthine/guanine. Deficiency: accumulation
toxic precursors → affects developing T cells more than B cells.
In both deficiencies: Development of lymphopenia (low levels lymphocytes) → progressive after
birth.
13-5 – Defects in DNA rearrangements
You can also get SCID by failures in DNA rearrangements in developing lymphocytes.
Mutations in RAG1/RAG2 → failure V(D)J recombination → arrest lymphocyte development.
Patients lack T and B cells.
, Hypomorphic mutations (reduce not absent function) of RAG1/RAG2 → small amount of functional
RAG protein → limited V(D)J recombination.
➔ Omenn syndrome: Children. Have hypomorphic mutations RAG1/RAG2. They are susceptible
for opportunistic infections and symptoms of graft-versus-host disease (rashes, diarrhoea,
enlargement lymph nodes). There is still some T cell receptor gene recombination but no B
cell receptor recombination → limited numbers T cells and lack B cells. T cells are
autoreactive (responsible for graft versus host).
➔ Other deficiencies reduced RAG activity: Granulomatous disease in late
childhood/adolescence.
Radiation sensitive SCID (RS-SCID): Subset of patients with autosomal recessive SCID have an
abnormal sensitivity to ionizing radiation → failure DNA rearrangement (very few, most abnormal)
→ very few mature B and T cells. There is a defect in DNA repair proteins involved in repairing
double stranded DNA breaks (during rearrangement and ionizing radiation). These patients are more
likely to develop cancer.
13-6 – Defects by interference TCR signalling
SCID can also be caused by interference with signalling through the T cell receptor:
• Patients with mutations in chains of CD3 complex → defective pre T cell receptor signalling
→ fail to progress to the double positive stage of thymic development → SCID.
• Patients with mutations in tyrosine phosphatase CD45 → reduction in peripheral T cell
numbers & abnormal B cell maturation.
• Patients make defective form cytosolic protein tyrosine kinase ZAP-70 (transmits signals
from T cell receptor) → CD8 T cells are absent & CD4 T cells fail to respond to stimuli that
normally activate the T cells through TCR.
Wiskott-Aldrich syndrome (WAS): Defect in WAS gene on the X chromosome that encodes WAS
protein (WASp). Affects platelets and reduces T cell numbers, defective NK-cell cytotoxicity and
failure of antibody responses. WASp is a key regulator of lymphocyte and platelet development
because it transduces receptor mediated signals that induce reorganisation of the cytoskeleton.
➔ Signalling pathways downstream TCR activate WASp → activates Arp2/3 → initiating actin
polymerisation → immune synapse formation & release effector molecules by T cells.
WASp also required for suppressive function of Tregs → patients susceptible to autoimmune
diseases.
13-7 – Defects in thymic function/MHC
Nude: SCID and no body hair. Mutation in FOXN1 which is a transcription factor expressed in skin &
thymus. Necessary for differentiation thymic epithelium & functional thymus → no thymic function
→ prevents normal T cell development & deficient B cell responses because of the lack of T cells.
DiGeorge syndrome: Thymic epithelium fails to develop normally → T cells cannot mature &
impaired antibody production. Deletion in 1 copy of chromosome 22 → deleted TBX1 which codes
transcription factor T-box1 → haploinsufficient for TBX1.
Bare lymphocyte syndrome/MHC II deficiency: Thymus lacks MHC II → CD4 T cells cannot be
positively selected and few develop. APCs also lack MHC II → the few developed CD4 T cells cannot
be stimulated. Caused by mutations in gene regulatory proteins required for transcriptional
system – Robin van Bruggen
13-3
Severe combined immunodeficiency (SCID): Patients with defects in T cell development. They have
no T cell dependent antibody responses or cell mediate immune responses and are susceptible to a
broad range of infectious agents.
X-linked SCID (XSCID, bubble boy): Most frequent form of SCID caused by mutations in IL2RG (X
chromosome, mostly male) which encodes for IL-2 receptor common gamma chain. This common
gamma chain is required for IL-2/4/7/9/15/21 and so patients have defects in signalling of all these
cytokines. T cells and NK cells fail to develop → cannot help B cells anymore → abnormal B cell
function. They don’t make effective antibody responses.
➔ Female XSCID patients inactivate defective X chromosome in naive IgM B cells → B cell
development is affected by, but not wholly dependent on the common gamma chain.
Kinase Jak3 SCID: Inactivating mutation in Jak3, this physically associates with common gamma
chain and transduces signalling through the cytokine receptors. It has the same effects as XSCID.
Mice with mutations in IL-15 (or the alfa chain of the receptor) have no NK cells and have a defect in
the maintenance of memory CD8 T cells.
Humans with a deficiency of IL-7 receptor alfa chain have no T cells (but do have NK cells) → IL-7
signalling is essential for T cell development (and not NK).
➔ Mice with a deficiency in IL-7 receptor have no T cells & B cells → species specific role
cytokines.
Humans & mice with defective production IL-2 → impaired development FoxP3 Tregs →
autoimmunity.
13-4 – Defects in enzymes
There are also autosomal recessive variants of SCID due to defects in enzymes like adenosine
deaminase (ADA) deficiency & purine nucleotide phosphorylase (PNP) deficiency.
• ADA: Conversion adenosine/deoxyadenosine → inosine/deoxyinosine. Deficiency:
accumulation of deoxyadenosine (and precursor S-adenosylhomocysteine) which are toxic to
developing T and B cells.
• PNP: Conversion of inosine/guanosine to hypoxanthine/guanine. Deficiency: accumulation
toxic precursors → affects developing T cells more than B cells.
In both deficiencies: Development of lymphopenia (low levels lymphocytes) → progressive after
birth.
13-5 – Defects in DNA rearrangements
You can also get SCID by failures in DNA rearrangements in developing lymphocytes.
Mutations in RAG1/RAG2 → failure V(D)J recombination → arrest lymphocyte development.
Patients lack T and B cells.
, Hypomorphic mutations (reduce not absent function) of RAG1/RAG2 → small amount of functional
RAG protein → limited V(D)J recombination.
➔ Omenn syndrome: Children. Have hypomorphic mutations RAG1/RAG2. They are susceptible
for opportunistic infections and symptoms of graft-versus-host disease (rashes, diarrhoea,
enlargement lymph nodes). There is still some T cell receptor gene recombination but no B
cell receptor recombination → limited numbers T cells and lack B cells. T cells are
autoreactive (responsible for graft versus host).
➔ Other deficiencies reduced RAG activity: Granulomatous disease in late
childhood/adolescence.
Radiation sensitive SCID (RS-SCID): Subset of patients with autosomal recessive SCID have an
abnormal sensitivity to ionizing radiation → failure DNA rearrangement (very few, most abnormal)
→ very few mature B and T cells. There is a defect in DNA repair proteins involved in repairing
double stranded DNA breaks (during rearrangement and ionizing radiation). These patients are more
likely to develop cancer.
13-6 – Defects by interference TCR signalling
SCID can also be caused by interference with signalling through the T cell receptor:
• Patients with mutations in chains of CD3 complex → defective pre T cell receptor signalling
→ fail to progress to the double positive stage of thymic development → SCID.
• Patients with mutations in tyrosine phosphatase CD45 → reduction in peripheral T cell
numbers & abnormal B cell maturation.
• Patients make defective form cytosolic protein tyrosine kinase ZAP-70 (transmits signals
from T cell receptor) → CD8 T cells are absent & CD4 T cells fail to respond to stimuli that
normally activate the T cells through TCR.
Wiskott-Aldrich syndrome (WAS): Defect in WAS gene on the X chromosome that encodes WAS
protein (WASp). Affects platelets and reduces T cell numbers, defective NK-cell cytotoxicity and
failure of antibody responses. WASp is a key regulator of lymphocyte and platelet development
because it transduces receptor mediated signals that induce reorganisation of the cytoskeleton.
➔ Signalling pathways downstream TCR activate WASp → activates Arp2/3 → initiating actin
polymerisation → immune synapse formation & release effector molecules by T cells.
WASp also required for suppressive function of Tregs → patients susceptible to autoimmune
diseases.
13-7 – Defects in thymic function/MHC
Nude: SCID and no body hair. Mutation in FOXN1 which is a transcription factor expressed in skin &
thymus. Necessary for differentiation thymic epithelium & functional thymus → no thymic function
→ prevents normal T cell development & deficient B cell responses because of the lack of T cells.
DiGeorge syndrome: Thymic epithelium fails to develop normally → T cells cannot mature &
impaired antibody production. Deletion in 1 copy of chromosome 22 → deleted TBX1 which codes
transcription factor T-box1 → haploinsufficient for TBX1.
Bare lymphocyte syndrome/MHC II deficiency: Thymus lacks MHC II → CD4 T cells cannot be
positively selected and few develop. APCs also lack MHC II → the few developed CD4 T cells cannot
be stimulated. Caused by mutations in gene regulatory proteins required for transcriptional
