T-Cell Deficiency Disorders, Inherited

 

Clinical Background

Cell-mediated immunity is mediated by T-lymphocytes (T-cells) and their effector response and interactions with other immune cells. Several inherited T-cell disorders have been identified.

T-cell immunodeficiency diseases include

  • Ataxia telangiectasia
  • Chronic mucocutaneous candidiasis
  • DiGeorge syndrome
  • Severe combined immunodeficiencies (SCID)
  • Wiskott-Aldrich syndrome (WAS)
  • Adenosine deaminase deficiency
  • Purine nucleoside phosphorylase deficiency

Epidemiology

  • Incidence – rare disorders <1/1,000,000
  • Age – most common during neonatal period and infancy
    •  Adult onset rare
  • Sex – M:F, equal, except X-linked diseases
    • M>F, for X-linked SCID and WAS

Inheritance

  • Autosomal recessive for all diseases except X-linked SCID and WAS

Pathophysiology

  • Defective lymphocyte responses may occur to stimulants
    • Nonspecific mitogens (PHA, Con A and PWM)
    • Specific antigens, such as Candida or tetanus
  • Characterized by increased susceptibility to infections from opportunistic organisms
    • Cytomegalovirus (CMV)
    • Candida albicans
    • Pneumocystis carinii

Clinical Presentation

  • SCID
    • Early onset of severe infections (intracellular bacterial, viral, fungal, Pneumocystis)
    • Growth failure
    • Persistent diarrhea
    • Occurrence of graft-versus-host disease upon exposure to maternal lymphocytes or blood transfusions
    • Earliest onset in X-linked SCID, adenosine deaminase (ADA) deficiency, purine nucleoside phosphorylase deficiency (PNP), ZAP70 defects, and T- and B-cell variants

      T- and B-cell Variants of SCID

      Variant

      T-cell

      B-cell

      NK-cell

      Comment

      IL2RG

      +

       

      JAK3

      +

       

      IL7R2

      +

      +

      T-cell growth IL7

      ADA

      Adenosine is toxic to all cells; depresses all cells

      PNP

      +

       

      RAG1 and RAG2

      +

      Recombinant of T- and B-cell receptors

      ARTEMIS

      +

      Recombinant of T- and B-cell receptors

      CD3D or CD3E

      +

      +

      T-cell receptors only

      CD45

      +

      +

      T-cell receptors only

      ZAP70CD4 (-)
      CD8 (+)
      Lymphocytes
      + 
  • DiGeorge syndrome
    • Recurrent infections – fungal, viral, bacterial, Pneumocystis
    • Congenital heart disease
    • Hypocalcemic tetany
    • Abnormal facies
    • Palatal abnormalities
    • Thymic hypoplasia
  • WAS
    • Recurrent infections – viral, pneumococcal
    • Eczema
    • Associated autoimmune disease common
  • Ataxia telangiectasia
    • Recurrent infections – sinopulmonary are most common
    • Progressive cerebellar dysfunction
    • Oculocutaneous telangiectasia
  • Chronic mucocutaneous candidiasis
    • Persistent or recurrent Candida infections of the skin, nails and mucous membranes
    • Often have an associated autoimmune disease
    • May be associated with multiple endocrinopathies

Treatment

  • Patients with severe T-cell defects, such as SCID, may be appropriate candidates for bone marrow or stem cell transplants and possibly gene therapy
  • Evaluation in the first 2-3 months of life treatment may decrease morbidity and mortality