T-cell deficiencies

Question 1

Deficiencies in T-cells can be…

Answer 1

• Deficiencies in lymphocyte production (SCID)
• Failure of thymic development (DiGeorge Syndrome)
• Failure of HLA expression (Bare lymphocyte syndrome)
• Failure of signalling, cytokine production and effector functions (Deficiency in IL-12, IFNy, IL12R or IFNyR)

Question 2

SCID - pathophysiology

Answer 2

Severe combined immunodeficiency (SCID)
Failure of production of lymphoid progenitors
This can be use to:
- Defective cytokine receptors
- Defective signalling
- Metabolic defects

Most common form in X-linked SCID (45%) followed by ADA deficiency SCID (16%).

Question 3

X-linked SCID

Answer 3

• Responsible for 45% SCID.
• Mutation in common gamma chain of the IL-12 receptor
• This is shared by multiple cytokines so cells cannot respond to these cytokines

This results in:

• Poorly developed lymphoid tissue
• Low T-cells
• Low NK cells
• Normal/high B-cells (with low Igs)

Question 4

ADA Deficiency SCID (16.5%)

Answer 4

There is deficiency in the adenosine deaminase enzyme (required for cell metabolism and maturation)

This results in:

• Low T-cells
• Low B-cells
• Low NK cells

Management - can give PEG-ADA

Question 5

SCID presentation

Answer 5

• Presents by 3mo age (until then, protected by maternal antibodies)

There is:

• FTT
• Persistent diarrhoea
• Unusual skin rash (colonisation of empty bone marrow with maternal cells)
• GvHD

Question 6

DiGeorge Syndrome

Answer 6

• Disorder of thymic maturation
• There is deletion at 22.11q2 which affects development of the pharyngeal pouch

Congenital features (CATCH-22)

• Congenital heart disease (Tetralogy of Fallot)
• Atypical facies (low-set ears, high forehead)
• Thymic aplasia
• CLAP
• Hypocalcaemia/hypoparathyroidism
• 22 (chromosome)

Presentation

• Normal B-cells with low T-cells
• Over time T-cell count improves as there is homeostatic increase
• Can potentially treat with thymic transplantation to help in the years before T-cells rise

Question 7

Bare lymphocyte syndrome Type 2

Answer 7

Pathophyiology:

• Defect in the regulatory proteins involved in HLA Class II expression (regulatory factor X, or Class II transactivator)
• Absent HLA Class II molecules
• This means that CD4+ T-cells cannot develop and B-cells cannot undergo isotype switching

Low CD4+ count, normal CD8+ count and Low IgA, IgG and IgE

Presentation:

• Unwell by 3mo age
• FTT
• Fhx early infant death
• May be associated with sclerosing cholangitis

Question 8

Bare lymphocyte syndrome Type 1

Answer 8

• Deficiency in expression of HLA Class I molecules

- The CD8+ T-cells cannot develop

Question 9

Deficiency in Cytokine Production by T-cells

Answer 9

• Deficiency of IL-12, IFNy and their receptors
• There is susceptibility to infection with mycobacteria, BCG and Salmonella
• Inability to form granulomas

Question 10

Features of T-cell deficiencies

Answer 10

• Susceptibility to viral and fungal infections
• Early malignancy
• Susceptible to intracellular pathogens e.g. Salmonella, Mycobacteria

Question 11

Investigations for T-cell deficiencies

Answer 11

• FBC, WBC and Differentials
• Lymphocyte subsets (CD4+, CD8+, B-cells, NK cells) is done by FACS (Fluorescent activated cell sorting)
• If there is low CD4+, check Ig levels
• Functional tests of T-cell activation and proliferation
• HIV test