Implications/Analysis of Family History

An inquiry into Mark’s family history revealed that two cousins (one male and one female) as well as a great-grandparent had presented with similar recurrent infections, suggesting a possible autosomal recessive inheritance for this disorder.

Implications/Analysis of Clinical History

A defect in phagocytes, leukocyte trafficking, or complement could account for the bacterial infections, but they would not, alone, account for other types of infection. A clinical history of fungal or viral infections strongly suggested a defect in T cell function. Therefore, a defect that affects both B cells and T cells should be considered.

Implications/Analysis of Laboratory Investigation

A normal white blood cell count and differential suggests that the problem is not in cell development. Additionally, an absolute deficiency in any cell population can be ruled out. However, subset analysis of T cells revealed a paucity of CD4+ T cells, indicating that the defect was evident at the level of CD4+ but not CD8+ T cells. Although B cell numbers are normal, serum immunoglobulin levels are low, which is not surprising given the relative CD4+ lymphopenia. However, we cannot rule out a B cell functional defect. A decrease in the number of CD4+ T cells and the pattern of infections is highly suggestive of HIV infection. This would not, however, account for the familial nature of the disease.

Additional Laboratory Tests

Serologic testing using an ELISA ruled out HIV as a cause of the low CD4+ T cell count. Flow cytometric analysis of various cell surface markers on T cells did not reveal any deficiencies. Analysis of B cell markers indicated a deficiency in expression of cell surface class II MHC proteins. Class II MHC heterodimers are constitutively expressed on antigen-presenting cells, where they display antigen fragments to CD4+ T cells (Fig. 9-1; see Antigen Recognition, later). Further analysis indicated that all antigen-presenting cells lacked expression of class II MHC. Because CD4+ T cells are only activated when they recognize the class II antigen complexes and because B cell activation requires CD4+ T cell help, a deficiency of class II on antigen-presenting cells alone could explain the reduction in B cell responses. Nevertheless, this does not explain the paucity of CD4+ T cells.

FIGURE 9-1 CD4+ T cells recognize antigen/MHC class II complexes on antigen-presenting cells. Activation of CD4+ T cells occurs after recognition of antigen/MHC class II complexes on antigen-presenting cells providing the appropriate co-stimulatory molecules are present.

(Modified with permission from Gorczynski R, Stanley J: Clinical Immunology. Austin, Landes, 1999.)

In the normal thymus, immature thymocytes co-express CD4 and CD8 during development. Progression to either single positive (CD4 or CD8) T cells requires the interaction of the T cell receptor with either class I or class II MHC present on the thymic epithelium. In the absence of class II MHC expression, developing thymocytes undergo either CD4 gene silencing to produce CD8+ T cells or remain as double positive (CD4+, CD8+) T cells. Thus, absence of class II expression results in defective development of CD4+ cells (as well as the other features described).

Prophylactic Treatment

Pharmacologic intervention is provided for infections as they arise. Prophylactic administration of intravenous gamma globulin therapy may be a consideration.

Bone Marrow Transplant

Although there have been reports of successful bone marrow transplants in young children with BLS, bone marrow transplant for these patients does not have the same success rate as has been reported for other disorders. This is not surprising in that expression of class II MHC on antigen-presenting cells is only of immunologic benefit if CD4+ T cells are present. CD4+ T cells are generated in the thymus, after interaction with class II MHC on the thymic epithelium (see earlier). Full reconstitution would thus depend on replacement of host thymic epithelium (as well as thymic stem cells) by donor marrow.

Patients with BLS have normal numbers of circulating T cells, but most of them are CD8+. The fact that there are a few patients with low numbers of circulating CD4+ T cells may be explained from studies with mice in which mice with defects in one of the trimeric complex proteins (RFX5, see later) express very low levels of MHC class II in the thymic cortex. Because fewer than 100 patients have been identified with BLS, it is difficult to investigate these issues in patient populations.

Gene Therapy

Although it is technically possible to introduce the gene for CIITA (ex vivo) into antigen-presenting cells that have been removed from the patient, as discussed earlier, this would not correct the problem leading to defective CD4+ T cell development. In contrast, in utero gene transfer should, in theory, lead to the expression of class II MHC on the thymic epithelial cells as well as on antigen-presenting cells. However, to overcome the problem in a young infant is a challenge, because of the limitations in gene delivery to targeted tissues, particularly the thymic cortex. Furthermore, constitutive expression of class II MHC in tissues that would not normally express this heterodimer could serve as a stimulus for inappropriate immune responses, leading to autoimmunity.

Role of CIITA

Although several roles have been postulated for CIITA as a master regulator, the most simplistic is that it functions as a scaffold (via protein-protein interactions) for recruitment of other factors required for transcription of class II genes. CIITA is also required for expression of the genes that encode Ii, the invariant chain, HLA-DM and HLA-DO, which play a role in intracellular trafficking and peptide loading of class II MHC.

CIITA is constitutively expressed in antigen-presenting cells and upregulated by IFNγ. De novo expression of class II MHC may also occur in non–antigen-presenting cells after stimulation with IFNγ. The expression of IFNγ-induced class II MHC can be inhibited in the presence of cytokines (TGFβ, IL-4, IL-10, and IL-1β), reflecting the role that CIITA plays in an immune response. In the absence of class II MHC/peptide on the cell surface, CD4+ T cells cannot be activated. Interestingly, some pathogens (Chlamydia species, Mycobacterium bovis, cytomegalovirus, varicella-zoster virus) have acquired immunoevasive strategies that result in the inhibition of IFNγ-induced expression of CIITA and hence of class II MHC expression. Of clinical interest is the report that statins, lipid-lowering drugs, inhibit IFNγ-induced class II MHC.

CIITA and Nucleotide Oligomerization Domain Protein

CIITA is now known to belong to a family of molecules having in common a nucleotide oligomerization domain (NOD) responsible for self-self protein interactions, which are apparently essential for signaling function from these interacting molecules. The most important proteins bound by CIITA are not well characterized, although a number of nuclear factors have been shown to bind to it (including cyclic adenosine monophosphate response element binding protein [CREB]). The mutations in CIITA that affect its role may, in fact, reflect defective NOD functioning.

Antigen Recognition

T cell receptors (TCRs) are heterodimers expressed on the cell surface in association with five invariant polypeptides collectively termed CD3. These heterodimers recognize antigenic peptides complexed with MHC proteins. Two broad classes of proteins encoded by the MHC loci are referred to as class I MHC proteins, which are expressed on all nucleated cells, and class II MHC proteins, which are constitutively present on antigen-presenting cells. T cells that express the lineage-defining molecule CD8 recognize antigenic fragments complexed with class I MHC. In contrast, T cells that express the lineage-defining molecule CD4 recognize antigenic fragments complexed with class II MHC.