Human genetics of common mycobacterial infections.

There is increasing interest in and understanding of the role of human genetic factors controlling susceptibility/resistance to infectious diseases. This is of particular importance for the two most common mycobacterial infections, tuberculosis and leprosy, because this will allow a genetic dissection of antimycobacterial immunity and should open new fields of preventive and therapeutic measures. In this review we will initially discuss various methods of genetic epidemiology that have been and are being developed to identify human genes controlling infectious diseases, and then illustrate the findings obtained in the numerous studies performed in tuberculosis and leprosy. Although the most convincing results were observed for HLA-DR2 and NRAMP1 (or a closely linked gene) in pulmonary tuberculosis and leprosy subtypes and for a 10p13 locus in paucibacillary leprosy, the molecular basis of their effects remains to be established.

Genetics of susceptibility to leprosy.

The ancient disease of leprosy can cause severe disability and disfigurement and is still a major health concern in many parts of the world. Only a subset of those individuals exposed to the pathogen will go on to develop clinical disease and there is a broad clinical spectrum amongst leprosy sufferers. The outcome of infection is in part due to host genes that influence control of the initial infection and the host's immune response to that infection. Identification of the host genes that influence host susceptibility/resistance will enable a greater understanding of disease pathogenesis. In turn, this should facilitate development of more effective therapeutics and vaccines. So far at least a dozen genes have been implicated in leprosy susceptibility and a genome-wide linkage study has lead to the identification of at least one positional candidate. These findings are reviewed here.

Genetics of susceptibility to leprosy

The ancient disease of leprosy can cause severe disability and disfigurement and is still a major health concern in many parts of the world. Only a subset of those individuals exposed to the pathogen will go on to develop clinical disease and there is a broad clinical spectrum amongst leprosy sufferers. The outcome of infection is in part due to host genes that influence control of the initial infection and the host's immune response to that infection. Identification of the host genes that influence host susceptibility/resistance will enable a greater understanding of disease pathogenesis. In turn, this should facilitate development of more effective therapeutics and vaccines. So far at least a dozen genes have been implicated in leprosy susceptibility and a genome-wide linkage study has lead to the identification of at least one positional candidate. These findings are reviewed here.

Interleukin-12 amplifies the M. leprae hsp65-cytotoxic response in the presence of tumour necrosis factor-alpha and interferon-gamma generating CD56+ effector cells: interleukin-4 downregulates this effect.

Interleukin-12 (IL-12) is a major immunomodulatory cytokine that represents a functional bridge between the early resistance and the subsequent antigen specific adaptive immunity. TNF-alpha and IFN-gamma have an important role in the generation of hsp65 specific cytotoxic T lymphocytes (CTL) that lyse hsp65-pulsed autologous macrophages (hsp65 CTL). Since a positive feedback mechanism between TNF-alpha, IFN-gamma and IL-12 has been described, we undertook to evaluate the role of IL-12 on the hsp65 CTL generation in leprosy patients. Our results show that the presence of IL-12 during the first 24 h of the in vitro antigen stimulation amplifies the hsp65 cytotoxic response whenever both IFN-gamma and TNF-alpha are present. The addition of these three cytokines (CKs) was able to abrogate the inhibitory effect of IL-10 on hsp65 CTL in cells from paucibacillary patients (PB) but not that of IL-4 in PB and normal controls (N). Both IL-12 or anti IL-4 enhanced the cytotoxic activity in cells from multibacillary patients (MB). Anti IL-4 upregulated the binding of IFN-gamma and did not modify that of TNF-alpha so the low CTL activity could be as a result of IL-4 by a decrease of the IFN-gamma binding on MB cells. Cells from those MB patients taking thalidomide (MB-T) did neither bind IFN-gamma nor TNF-alpha even when antigen or anti-IL-4 were added, demonstrating that thalidomide inhibits either the in vitro binding or receptor expression of both TNF-alpha and IFN-gamma. Development of CD56 effector cells during the hsp65 stimulation was observed in PB and N by the addition of IL-12 plus TNF-alpha and IFN-gamma, while in MB and MB-T anti IL-4 was also required. So, the inhibitory effect of IL-4 on either production of IFN-gamma, TNF-alpha and/or IL-12 or their receptors could be the mechanism underlying the lack of the hsp65 CTL generation in cells from MB.

Epitope specificity and MHC restriction of rheumatoid arthritis synovial T cell clones which recognize a mycobacterial 65 kDa heat shock protein.

CD4+ T cell clones specific for the mycobacterial hsp 65 were obtained from synovial fluid of a DR4 homozygous rheumatoid arthritis (RA) patient. A stimulatory epitope was defined using both deletion mutants of the mycobacterial hsp 65 and synthetic peptides and proved to be in a highly conserved region of the molecule. Despite this, however, there was no recognition by these clones of either the recombinant human homologue of mycobacterial hsp 65, P60, nor of a synthetic peptide containing an amino acid sequence from P60 corresponding to the epitope defined in the mycobacterial hsp 65. When the pattern of HLA restriction shown by the hsp-65-specific T cell clones was investigated, all clones tested proved to be restricted by HLA-DP rather than the more usual HLA-DR. Inhibition experiments suggested that this restriction also applied to the polyclonal synovial T cell response to hsp 65, but not to other antigens. Exclusive restriction of T cell recognition of an antigen by HLA-DP has not been reported previously, and strongly suggests that in this case the T cell repertoire for recognizing hsp 65 in the context of DR4 is deficient. Such an association between DR4 and the inability to respond to an immunodominant bacterial antigen may have implications for the pathogenesis of RA.