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Chapter: Medical Immunology: Primary Immunodeficiency Diseases

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Other Forms of Combined Immune Deficiency

Combined Immunodeficiency with Immunoglobulins (Nezelof Syndrome), Immunodeficiency with Ataxia-Telangiectasia

Other Forms of Combined Immune Deficiency

1. Combined Immunodeficiency with Immunoglobulins (Nezelof Syndrome)


Clinically, this situation is very similar to those cases of SCID in which variable numbers of B lymphocytes and variable levels of immunoglobulins can be assayed. There is no well-defined pattern of inheritance. The evolution is usually more benign than in more severe forms of SCID, with survivals up to the teens.

2. Immunodeficiency with Ataxia-Telangiectasia


Genetics and Physiopathology.Ataxia-telangiectasia is genetically transmittedby an autosomal inheritance pattern. It is believed that the disease may result from a defi-ciency of DNA repair enzymes, as suggested by the high frequency of lymphoreticular ma-lignancies. In addition, the enzyme defect seems to result in a generalized defect in tissue maturation, affecting many tissues, but with particularly significance the brain capillary vessels. Persistently increased levels of serum α-fetoprotein and carcinoembryonic antigen in many patients with this disease support this last postulate.

Clinical Presentation.The initial symptoms are of progressive cerebellar ataxiabeginning in early childhood associated with insidiously developing telangiectasia (first appearing as a dilation of the conjunctival vessels). The capillary abnormalities are sys-temically distributed and involve the cerebellum, causing the motor difficulties character-istic of ataxia. In late childhood, recurrent sinobronchial infections start to manifest, lead-ing to bronchiectasis.

Associations of thymic hypoplasia, T-cell deficiency, and low immunoglobulin lev-els characterize this immunodeficiency. Low or undetectable IgA is reported in 80% of the patients.

The prognosis is poor and there is no effective therapy. Correction of the immune de-ficiency through bone marrow transplant does not alter the course of central nervous sys-tem deterioration. Death usually occurs before puberty, most frequently as a consequence of lymphoreticular malignancies or of the rupture of telangiectatic cerebral blood vessels.

3. IL-2 Synthesis Deficiency


Combined immunodeficiency associated with a deficiency in IL-2 synthesis and IL-2 re-ceptor can be seen in patients with congenital deficiency of CD4+ cells as well as in pa-tients with normal numbers of CD4+ cells.

Genetics and Physiopathology.In patients with congenital deficiency of CD4+ cells, the defect of IL-2 production and IL-2 receptor expression is a direct consequence of the lack of differentiation of this lymphocyte subpopulation. At least in one case of CD4+ deficiency, the CD4 gene was identified in the patient’s cells, although no transcription products could be detected. Thus, the defect may result either from minor gene alterations, undetectable by our current methodologies, or from lack of transcriptional activation of a normal gene.

In patients with normal numbers of CD4+ T cells, the defect can be found in a mu-tated IL-2 gene or in the system of second messenger molecules and transacting proteins (particularly NF-AT), which mediate the activation of cellular genes after antigenic or mi-togenic stimulation.

Clinical Presentation.In general the affected children have a very early onset ofsymptoms and suffer from both opportunistic and bacterial infections. Immunoglobulin lev-els tend to be decreased, and antibody responses after active immunization are subnormal.

Diagnosis.In cases of CD4+ deficiency these cells are absent or detected in verylow numbers. In cases due to abnormalities of the IL-2 gene or due to abnormalities in the signaling pathway that leads to expression of the IL-2 gene, the number of CD4+ cells may be normal. However, the peripheral blood lymphocytes fail to proliferate and to release IL-2 after stimulation with T-cell mitogens, antigens, or CD3 monoclonal antibodies. Defini-tive diagnosis requires investigation of the molecular defects underlying the disease.

4. Deficient Expression of MHC Molecules


The lack of expression of either MHC-I or MHC-II molecules is associated with combined immunodeficiency.

The bare lymphocyte syndrome (MHC-I deficiency) is characterized by a deficient expression of HLA-A, B, and C markers and absence of β2-microglobulin on lymphocyte membranes. In one family the defect has been localized to a mutation of one of the genes coding for one of the transporters associated with antigen processing (TAP-2), essential for proper intracellular assembly of the MHC-I molecules .

Although some patients with this syndrome may be asymptomatic, most suffer from infections. In some cases, the infection pattern involving fungi and Pneumocystis carinii is consistent with combined immunodeficiency; in other patients, the symptoms are mainly due to infections with pyogenic bacteria. The link between lack of expression of MHC class I markers and humoral immunodeficiency is unclear.

Laboratory findings include lymphopenia, poor mitogenic responses, low im-munoglobulin levels, and lack of antibody responses. B cells are usually detected, but plasma cells are absent.

MHC class II deficiency is inherited as an autosomal recessive trait, apparently re-sulting in abnormal transcription regulation of the MHC genes. It is associated with a se-vere form of combined immunodeficiency, with absent cellular and humoral immune re-sponses after immunization. These patients have low number of CD4+ helper T lymphocytes, which results in lack of differentiation of B lymphocytes into antibody-pro-ducing cells. This syndrome provides strong support for the theory suggesting that the in-teraction between double-positive CD4+ , CD8+ thymocytes and MHC-II molecules is the essential stimulus for the differentiation of CD4+ helper T lymphocytes.

The patients often have protracted diarrhea, secondary to infections with Candida al-bicans or Cryptosporidium parvum, leading to malabsorption and failure to thrive. Pul-monary infections are also frequent. Residual cytotoxic T-cell function is reflected by the ability of these children to reject grafted cells and tissues. The prognosis is very poor. Death tends to occur before the second decade of life unless the deficiency is corrected by bone marrow transplant.

Laboratory findings include normal counts of CD3+ lymphocytes associated to low numbers of CD4+ cells. The expression of MHC-II molecules in monocytes and/or B cells is absent or very low (less than 5% of normal). Definitive diagnosis requires molecular studies to characterize the responsible gene mutations.

5. Immunodeficiency with Thrombocytopenia and Eczema (Wiskott-Aldrich Syndrome)


Genetics and Pathogenesis.This is another immune disorder with an X-linked re-cessive pattern of inheritance. The associated gene has been located to Xp11.23, which en-codes the protein known as Wiskott-Aldrich syndrome protein (WASP). This protein is ex-pressed by hematopoietic cells and appears to play a role in actin polymerization and cytoskeleton arrangement. The mutations are associated with either lack of synthesis or with synthesis of an abnormal WASP. In the absence of functional WASP hematopoietic cells demonstrate abnormal size, shape, and function that is most apparent in platelets and lymphocytes. Platelets are small in size, aggregate poorly, and are sequestered and de-stroyed in the spleen. T lymphocytes are also smaller than normal and show disorganiza-tion of the cytoskeleton and loss of microvilli. Directed traffic of cytokines and expression of co-stimulatory molecules are likely to be affected.

Clinical Presentation.Eczema, thrombocytopenia, and frequent infections char-acterize the Wiskott-Aldrich syndrome. Most frequently the infections are caused by viruses, such as herpes simplex, varicella-zoster, and molluscum contagiosum. Increased frequency of infections with encapsulated pyogenic bacteria, such as Streptococcus pneu-moniae, Neisseria meningitidis, and Haemophilus influenzae, can also be seen. Later in lifepatients can suffer from all types of opportunistic infections, reflecting a deterioration of both cell-mediated and humoral immune functions. There is an increased frequency of au-toimmune diseases, particularly autoimmune hemolytic anemia and rheumatoid arthritis. Hemorrhage is the most frequent cause of death, but some children develop opportunistic infections or lymphoreticular malignancies that can have a fatal evolution.

Laboratory Findings.The finding of profound thrombocytopenia with small-sized platelets very early in life is often the first clinical sign of Wiskott-Aldrich syndrome. Platelets are characterized as small and dysmorphic. Definitive diagnosis requires either molecular studies revealing mutations of the WASP gene or absence of the WASP mRNA or WASP protein in peripheral blood lymphocytes.

Several laboratory abnormalities are characteristic of this immune deficiency. These include low IgM levels (the levels of the other immunoglobulin isotypes may be low, nor-mal, or elevated) and failure to respond to polysaccharide vaccines or to immunizations with neoantigens such as bacterial phage øx174 . Lymphocyte count and function are normal in early infancy, but deficient mitogenic and mixed lymphocyte cul-ture responses develop over time

Therapy.Thrombocytopenia improves following splenectomy. The immunologi-cal defects can be corrected by bone marrow transplantation. Replacement therapy with in-travenous gamma globulin has been used in some patients.

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