Immunology and AllergyTier 1Disease (DEADMAN)

Immunodeficiency syndromes - combined B- and T-cell immunodeficiencies

Description

SCID - profound defect of both cellular and humoral immunity
- A paediatric emergency: without HSCT, death in the first 1-2 years
Presentation: persistent thrush, chronic diarrhoea, failure to thrive, PJP, disseminated BCG or rotavirus after live vaccination, absent thymic shadow, absent tonsils/lymph nodes

Classification by immunophenotype - the exam frame

Phenotype	Defect	Example
T-B+NK-	IL2RG (common gamma chain), X-linked - the commonest form (~50%)	X-SCID
T-B+NK-	JAK3 (AR) - same pathway
T-B-NK+	RAG1/RAG2 (failed V(D)J recombination), Artemis	Omenn syndrome if hypomorphic
T-B-NK-	ADA deficiency - toxic metabolite accumulation	Also skeletal and neurological features
T-B+NK+	IL7RA

Less severe combined immunodeficiencies

Wiskott-Aldrich (X-linked, WAS gene) - eczema + thrombocytopenia with SMALL platelets + immunodeficiency; lymphoma and autoimmunity
Ataxia telangiectasia (ATM) - cerebellar ataxia, oculocutaneous telangiectasia, raised AFP, radiosensitivity, lymphoma
Hyper-IgM syndrome (CD40L, X-linked) - normal/high IgM, low IgG/IgA, PJP and cryptosporidium, neutropenia
22q11.2 deletion - partial combined defect

SCID results from loss of a component essential for T-cell generation or function
- Without T cells there is no help for B cells -> B cells present but non-functional -> combined defect
- Hence "T-B+" still means no useful antibody
The unifying mechanism in the commonest forms is loss of the ability to respond to cytokines, especially IL-7
- IL-7 signals through the common gamma chain (IL2RG) -> JAK3 -> STAT5
- Also shared by IL-2, -4, -9, -15, -21 (hence NK loss with IL-15 signalling failure)
- IL-7 is essential for thymocyte survival and proliferation -> its loss halts T-cell development
RAG1/RAG2: failed V(D)J recombination -> no antigen receptor -> no T or B cells
ADA deficiency: dATP accumulation -> lymphotoxic
Maternal T-cell engraftment or oligoclonal autologous T cells -> Omenn syndrome (erythroderma, hepatosplenomegaly, eosinophilia, alopecia)

Suspect in an infant with

Testing

Absolute lymphocyte count - lymphopenia (<2.8 x10^9/L in an infant) is the single best screening test and is routinely overlooked
TREC assay - newborn screening; low/absent TRECs = failed thymic output
Lymphocyte subsets -> assign the T/B/NK phenotype
Naive (CD45RA+) vs memory T cells - maternal engraftment gives memory-only T cells
Immunoglobulins (low, but maternal IgG persists to 3-6 months) and vaccine responses
Lymphocyte proliferation to PHA - absent
ADA/PNP enzyme assay; genetic panel/WES for definitive diagnosis
HLA typing of patient and family immediately

Treat as an emergency the moment SCID is suspected - outcome is time-critical.

A. Protective measures - immediately, before diagnosis is confirmed

Stop breastfeeding if mother is CMV-positive
No live vaccines, and none to household contacts (rotavirus, BCG, MMRV, oral polio)
Irradiated, CMV-negative, leucodepleted blood products only - non-irradiated products cause fatal transfusion-associated GVHD
Reverse isolation

B. Bridging therapy

C. Definitive

Allogeneic HSCT - the treatment of choice
- Survival >90% if transplanted before 3.5 months of age and before infection is established; falls to ~50-70% once infected
- -> the entire rationale for newborn TREC screening
Gene therapy - ADA-SCID (approved), X-SCID (lentiviral, self-inactivating vectors after early gammaretroviral leukaemogenesis)
PEG-ADA enzyme replacement as a bridge in ADA-SCID
Thymus transplantation for complete athymia (22q11.2)

D. Other combined defects

Wiskott-Aldrich: HSCT curative; avoid splenectomy where transplant is planned
Ataxia telangiectasia: supportive; avoid diagnostic ionising radiation - radiosensitive, malignancy surveillance
Hyper-IgM: Ig replacement + cotrimoxazole + boiled/filtered water (cryptosporidium); HSCT for CD40L deficiency

Untreated SCID is uniformly fatal, usually before 12-24 months
Post-HSCT outcome determined by age at transplant and infection status at transplant, not by donor source alone
Long-term post-HSCT issues
- Persistent B-cell dysfunction -> continued Ig replacement in a substantial minority (especially without conditioning)
- Growth, endocrine and neurocognitive effects of conditioning
- Chronic GVHD
Ataxia telangiectasia: progressive neurodegeneration, ~25% lifetime malignancy risk, median survival ~25 years
Wiskott-Aldrich untreated: median survival ~15 years - bleeding, infection, lymphoma

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