THE JOURNAL OF INFECTIOUS DISEASES. VOL. 139, NO.2. FEBRUARY 1979
NEWS From the National Institutes of Health Summary of a Workshop on the Major Histocompatibility Complex in Infectious Disease Epidemiology
Introduction
A considerable body of evidence is accumulating that suggests that the products of the genetic region known as the major histocompatibility complex (MHC) play an important role in the disease response to a variety of infectious This article is in the public domain. Please address requests for reprints to Dr. George T. Curlin, Chief, Epidemiology and Biometry Branch, National Institute of Allergy and Infectious Diseases, Room 739, Westwood Building, National Institutes of Health, Bethesda, Maryland 20014.
246
Downloaded from http://jid.oxfordjournals.org/ at Emory University on August 26, 2015
A workshop, sponsored by the National Institute of Allergy and Infectious Diseases, on the use of histocompatibility phenotype as a variable in epidemiologic studies of infectious diseases was held in Bethesda, Md., March 2 and 3, 1978. The chairman of the Workshop was J. Thomas Grayston; the group chairpeople and rapporteurs were John E. Craighead, R. Gordon Douglas, David T. Karzon, Wilma B. Bias, W. Paul Glezen, and Andre J. Nahmias. Those presenting were D. Bernard Amos, Rene R. P. de Vries, Robert Elston, William D. Hillis, John B. Robbins, Pablo Rubinstein, Julius Schachter, Paul I. Terasaki, Jon J. van Rood, and Edmond J. Yunis. Other participants included E. Russell Alexander, Philip S. Brachman, Mary J. Carter, Richard G. Cornell, John R. David, Earl L. Diaond, Roger Detels, David Drutz, Bo DuPont, King K. Holmes, William S. Jordan, Adel Mahmoud, William H. Marine, Robert W. McCollum, Kenneth McIntosh, Max R. Mickey, Arnold S. Monto, John N. Neff, Roger D. Rossen, and Donovan J. Thompson. The organizing committee consisted of David W. Alling, Carl Cohen, George T. Curlin, Raphael Dolin, Bernard W. Janicki, Albert Z. Kapikian, Eric A. Ottesen, Fred .J. Payne, and Ethan M. Shevach.
agents. While an MHC-mediated basis for susceptibility or resistance to bacterial, viral, and parasitic diseases has been demonstrated in mice, analogous evidence is less certain in humans. The human MHC antigens, better known as human leukocyte antigens (HLA), have been found to be correlated with one or another form of expression of infection with or sequelae of a limited number of infectious agents, including hepatitis B, measles, rubella, and vaccinia viruses, Chlamydia, Mycobacterium leprae, Yersinia enterocolitica, Haemophilus infiuenzae, Shigella, and Salmonella. The selective pressure resulting from a predisposition of persons with certain HLA types to malaria has been postulated as the cause of the differences in frequency of HLA phenotypes observed in study populations in Sardinia [1]. Few of these studies have been designed to show genetic linkage, however, and the mechanisms involved in the reported associations remain to be determined. Nevertheless, if these associations can be confirmed and their reliability as determinants of specific types of expression of infectious diseases established, determination of HLA phenotypes could be of great value both in the application of measures for the prevention and control of disease and in biomedical research generally. An important consideration for further definition of the extent of associations between HLA and disease is the degree to which the mechanisms may be polygenic. Two or more genes may be involved in an observed association, and only one of these may be linked to the HLA system. The mechanisms may be even more complex in that there may be multiple genes that are linked to HLA and others that are not. The interferon system is an example of a nonspecific immune mechanism that is known to depend on multiple genes on different chromosomes, none of which include the MHC. Thus, although specific HLA phenotypes have been associated statistically with diseases in humans, including the infections mentioned above, linkage has not been convincingly demonstrated
NIH News
247
tions caused by either conventional or unconventional viruses. In addition to the above classes of disease, immunoprophylactic studies with new polypeptide and polysaccharide vaccines that are defined on a molecular basis should be given priority. These studies characteristically include careful measurements of the immune response, and the addition of HLA typing could provide valuable new information at reasonable additional cost. New studies with live, attenuated virus vaccines should also be considered.
Workshop Report
Special Considerations
After considering the evidence currently available, the Workshop concluded that further investigations for association of histocompatibility antigens with infections are indicated. Epidemiologic experience coupled with the work on animal models is adequate to suggest an inherited basis for resistance and susceptibility to many infectious diseases, and the HLA system offers new tools for an orderly exploration of inherited factors. However, there are many opportunities for such studies, given the diversity of HLA markers and the number and variation in biological properties of infectious agents. Since our knowledge both of the molecular mechanisms and genetic linkages of the HLA system and of the genetic control of cellular immunity in humans is incomplete, these studies should be designed with care. The Workshop recommended that the following infectious diseases or conditions should receive priority for study: (1) those that have already shown significant association with specific histocompatibility phenotypes, (2) those that have or appear to have a hereditary or racial predisposition (e.g., disseminated coccidioidomycosis), (3) those that have sporadically occurring uncommon expressions or complications (e.g., paralytic poliomyelitis), (4) those whose expression is mediated by immunologic mechanisms (e.g., chronic active hepatitis), (5) immunologic diseases that may have an infectious component (e.g., the collagen vascular diseases), (6) post-infectious complications that may be immunologically mediated (e.g., rheumatic fever and Reye's syndrome), and (7) slow virus infec-
In establishment of relationships between infectious agents and genetic markers, there are many difficulties to consider. Many, if not most, of the infectious diseases in the United States are ubiquitous, and thus retrospective studies based on serologic techniques, for instance, mayor may not show some degree of association. The variability of disease presentation must be considered. A common infection may vary from silent acquisition of antibody to mild, severe, complicated, recurrent, or latent disease. Variables such as age, dose, and epidemiologic setting must be taken into account. The immune response should be measured by a variety of test systems that measure serum antibody as well as cellular immunity or suppression: in a study of smallpox immunization in Dutch military recruits, HLA association was demonstrated when a test of cellular immunity was employed but not when HAl was employed [2]. Epidemiologic Studies
The types of epidemiologic studies needed for establishment of either association or linkage between a disease or disorder and a genetic marker such as HLA phenotype were considered at length. Many of the early reports of association were derived from "quick and dirty" studies in which the frequencies of HLA phenotypes in cases were measured and compared with the frequencies of these phenotypes in studies of "normal" populations instead of in controls. While such studies have been of value in calling attention to possible associations, they are by their
Downloaded from http://jid.oxfordjournals.org/ at Emory University on August 26, 2015
by studies of families. If the HLA phenotypes are to serve as reliable markers for MHC-linked disease susceptibility genes, formal linkage should be established by family studies. However, the MHC may play an important role in susceptibility or resistance to disease whether or not the "susceptibility" or "resistance" genes are linked to the human MHC. In such instances strong associations may be of predictive value for clinicians, although evidence for linkage is either lacking or negative.
248
Study Populations
Populations that should receive priority for study of relationships between HLA and disease are those which have already been HLA-typed for other kinds of genetic studies. If appropriate studies of infectious disease could be superimposed on such populations, a maximal amount of information could be obtained at relatively low cost. A second group of populations to be preferred for study would include those which have been or are currently under study for infectious diseases of one type or another, such as popula-
tions established for vaccine trials or for surveillance of specific diseases. The cost of adding HLA typing to such studies would not be excessive in terms of the overall costs of the studies themselves and the value of the additional information to be derived from them. Summary
The Workshop concluded that, with the reservations cited above, further work to associate histocompatibility antigens with infection is appropriate. It was felt that these efforts should be carried out deliberately and with careful planning rather than in a "screening" fashion. Existing leads should receive detailed exploration of the mechanisms in vitro. Diseases that should receive highest priority for future studies include: (1) those that have been associated with histocompatibility antigens thus far, (2) conditions that have an established hereditary or racial predisposition, and (3) those that have sporadic and unusual expressions or complications. It was clear in the discussion that emphasis should focus on populations from which maximal genetic information can be derived, i.e., family groups, sibships, or twinships. Twinships provide the opportunity to exclude environmental factors, whereas family groups and sibships provide an opportunity to demonstrate nonrandom segregation of HLA haplotypes in relation to infection. It was noted that there have been a number of populations developed for prospective epidemiologic surveys of families for infectious diseases that might be investigated further. Determination of HLA haplotypes of families in such studies would be relatively inexpensive, although the analysis of the relationships with various minor infections could be challenging. In addition, certain geographically restricted or closed population groups that have already been defined as to their histocompatibility patterns could be profitably employed for prospective studies of the relationship between HLA and infection. Finally, the Workshop recommended that future immunization studies for assay of new or prospective vaccines in both children and adults be conducted in family groups that can be HLA-typed. This would provide a unique op-
Downloaded from http://jid.oxfordjournals.org/ at Emory University on August 26, 2015
very nature inconclusive. It was agreed that the value of further studies of this kind would be very limited. Better developed case-control studies using carefully matched controls, especially where the controls include at least two siblings, are most appropriate for uncommon disorders such as rheumatic fever or Reye's syndrome. When practical by virtue of the prevalence of the disease, twin studies using monozygotic twins are especially useful when there is a need to discriminate between genetic and environmental factors in disease expression. The preferable type of study, whenever practicable, is the prospective study in which families or their appropriate members are used as the units of the cohort. Utilizing well-defined descriptors of the clinical and immunologic characteristics of the disorder along with HLA phenotype determination, such studies promise to yield the maximal amount of information with regard to the degree of association, the genetic contribution to the disorder in question, and the definition of nonrandom segregation of the disease with the genetic markers included for study. The alternative to this type of study would utilize individuals rather than families as the units for selection into the cohort. Such studies may be of less value since the information to be derived would concern associations between HLA and disease only without concomitant genetic information. By the same token, retrospective studies should recognize the unreliability of many of the determinants of both infection and immunity in episodes for which time of occurrence cannot be established.
Grayston and Payne
NIH News
249
portunity to assess various forms of immunologic responsiveness associated with histocompatibility genes.
J. THOMAS GRAYSTON Vice President for Health Affairs University of Washington Seattle) Washington FRED
J. PAYNE
1. Piazza, A., Belvedere, M. C., Bernoco, D., Conighi, C., Contu, L., Curtoni, E. S., Mattinz, P. L., Mayr, W.; Richiardi, P., Scudeller, G., Ceppellini, R. HL-A variation in four Sardinian villages under differential selective pressure by malaria. In Histocompatibility testing 1972. Munksgaard, Copenhagen, 1972, p. 73-84. 2. De Vries, R. R. P., Kreeftenberg, H. K., Loggen, H. G., van Rood, J. J. In vitro immune responsiveness to vaccinia virus and HLA. N. Eng!. J. Med. 297:692-696, 1977.
Downloaded from http://jid.oxfordjournals.org/ at Emory University on August 26, 2015
Research Epidemiologist Epidemiology and Biometry Branch Microbiology and Infectious Diseases Program National Institute of Allergy and Infectious Diseases National Institutes of Health
References
NEWS From the National Institutes of Health Summary of a Workshop on the Major Histocompatibility Complex in Infectious Disease Epidemiology
Introduction
A considerable body of evidence is accumulating that suggests that the products of the genetic region known as the major histocompatibility complex (MHC) play an important role in the disease response to a variety of infectious This article is in the public domain. Please address requests for reprints to Dr. George T. Curlin, Chief, Epidemiology and Biometry Branch, National Institute of Allergy and Infectious Diseases, Room 739, Westwood Building, National Institutes of Health, Bethesda, Maryland 20014.
246
Downloaded from http://jid.oxfordjournals.org/ at Emory University on August 26, 2015
A workshop, sponsored by the National Institute of Allergy and Infectious Diseases, on the use of histocompatibility phenotype as a variable in epidemiologic studies of infectious diseases was held in Bethesda, Md., March 2 and 3, 1978. The chairman of the Workshop was J. Thomas Grayston; the group chairpeople and rapporteurs were John E. Craighead, R. Gordon Douglas, David T. Karzon, Wilma B. Bias, W. Paul Glezen, and Andre J. Nahmias. Those presenting were D. Bernard Amos, Rene R. P. de Vries, Robert Elston, William D. Hillis, John B. Robbins, Pablo Rubinstein, Julius Schachter, Paul I. Terasaki, Jon J. van Rood, and Edmond J. Yunis. Other participants included E. Russell Alexander, Philip S. Brachman, Mary J. Carter, Richard G. Cornell, John R. David, Earl L. Diaond, Roger Detels, David Drutz, Bo DuPont, King K. Holmes, William S. Jordan, Adel Mahmoud, William H. Marine, Robert W. McCollum, Kenneth McIntosh, Max R. Mickey, Arnold S. Monto, John N. Neff, Roger D. Rossen, and Donovan J. Thompson. The organizing committee consisted of David W. Alling, Carl Cohen, George T. Curlin, Raphael Dolin, Bernard W. Janicki, Albert Z. Kapikian, Eric A. Ottesen, Fred .J. Payne, and Ethan M. Shevach.
agents. While an MHC-mediated basis for susceptibility or resistance to bacterial, viral, and parasitic diseases has been demonstrated in mice, analogous evidence is less certain in humans. The human MHC antigens, better known as human leukocyte antigens (HLA), have been found to be correlated with one or another form of expression of infection with or sequelae of a limited number of infectious agents, including hepatitis B, measles, rubella, and vaccinia viruses, Chlamydia, Mycobacterium leprae, Yersinia enterocolitica, Haemophilus infiuenzae, Shigella, and Salmonella. The selective pressure resulting from a predisposition of persons with certain HLA types to malaria has been postulated as the cause of the differences in frequency of HLA phenotypes observed in study populations in Sardinia [1]. Few of these studies have been designed to show genetic linkage, however, and the mechanisms involved in the reported associations remain to be determined. Nevertheless, if these associations can be confirmed and their reliability as determinants of specific types of expression of infectious diseases established, determination of HLA phenotypes could be of great value both in the application of measures for the prevention and control of disease and in biomedical research generally. An important consideration for further definition of the extent of associations between HLA and disease is the degree to which the mechanisms may be polygenic. Two or more genes may be involved in an observed association, and only one of these may be linked to the HLA system. The mechanisms may be even more complex in that there may be multiple genes that are linked to HLA and others that are not. The interferon system is an example of a nonspecific immune mechanism that is known to depend on multiple genes on different chromosomes, none of which include the MHC. Thus, although specific HLA phenotypes have been associated statistically with diseases in humans, including the infections mentioned above, linkage has not been convincingly demonstrated
NIH News
247
tions caused by either conventional or unconventional viruses. In addition to the above classes of disease, immunoprophylactic studies with new polypeptide and polysaccharide vaccines that are defined on a molecular basis should be given priority. These studies characteristically include careful measurements of the immune response, and the addition of HLA typing could provide valuable new information at reasonable additional cost. New studies with live, attenuated virus vaccines should also be considered.
Workshop Report
Special Considerations
After considering the evidence currently available, the Workshop concluded that further investigations for association of histocompatibility antigens with infections are indicated. Epidemiologic experience coupled with the work on animal models is adequate to suggest an inherited basis for resistance and susceptibility to many infectious diseases, and the HLA system offers new tools for an orderly exploration of inherited factors. However, there are many opportunities for such studies, given the diversity of HLA markers and the number and variation in biological properties of infectious agents. Since our knowledge both of the molecular mechanisms and genetic linkages of the HLA system and of the genetic control of cellular immunity in humans is incomplete, these studies should be designed with care. The Workshop recommended that the following infectious diseases or conditions should receive priority for study: (1) those that have already shown significant association with specific histocompatibility phenotypes, (2) those that have or appear to have a hereditary or racial predisposition (e.g., disseminated coccidioidomycosis), (3) those that have sporadically occurring uncommon expressions or complications (e.g., paralytic poliomyelitis), (4) those whose expression is mediated by immunologic mechanisms (e.g., chronic active hepatitis), (5) immunologic diseases that may have an infectious component (e.g., the collagen vascular diseases), (6) post-infectious complications that may be immunologically mediated (e.g., rheumatic fever and Reye's syndrome), and (7) slow virus infec-
In establishment of relationships between infectious agents and genetic markers, there are many difficulties to consider. Many, if not most, of the infectious diseases in the United States are ubiquitous, and thus retrospective studies based on serologic techniques, for instance, mayor may not show some degree of association. The variability of disease presentation must be considered. A common infection may vary from silent acquisition of antibody to mild, severe, complicated, recurrent, or latent disease. Variables such as age, dose, and epidemiologic setting must be taken into account. The immune response should be measured by a variety of test systems that measure serum antibody as well as cellular immunity or suppression: in a study of smallpox immunization in Dutch military recruits, HLA association was demonstrated when a test of cellular immunity was employed but not when HAl was employed [2]. Epidemiologic Studies
The types of epidemiologic studies needed for establishment of either association or linkage between a disease or disorder and a genetic marker such as HLA phenotype were considered at length. Many of the early reports of association were derived from "quick and dirty" studies in which the frequencies of HLA phenotypes in cases were measured and compared with the frequencies of these phenotypes in studies of "normal" populations instead of in controls. While such studies have been of value in calling attention to possible associations, they are by their
Downloaded from http://jid.oxfordjournals.org/ at Emory University on August 26, 2015
by studies of families. If the HLA phenotypes are to serve as reliable markers for MHC-linked disease susceptibility genes, formal linkage should be established by family studies. However, the MHC may play an important role in susceptibility or resistance to disease whether or not the "susceptibility" or "resistance" genes are linked to the human MHC. In such instances strong associations may be of predictive value for clinicians, although evidence for linkage is either lacking or negative.
248
Study Populations
Populations that should receive priority for study of relationships between HLA and disease are those which have already been HLA-typed for other kinds of genetic studies. If appropriate studies of infectious disease could be superimposed on such populations, a maximal amount of information could be obtained at relatively low cost. A second group of populations to be preferred for study would include those which have been or are currently under study for infectious diseases of one type or another, such as popula-
tions established for vaccine trials or for surveillance of specific diseases. The cost of adding HLA typing to such studies would not be excessive in terms of the overall costs of the studies themselves and the value of the additional information to be derived from them. Summary
The Workshop concluded that, with the reservations cited above, further work to associate histocompatibility antigens with infection is appropriate. It was felt that these efforts should be carried out deliberately and with careful planning rather than in a "screening" fashion. Existing leads should receive detailed exploration of the mechanisms in vitro. Diseases that should receive highest priority for future studies include: (1) those that have been associated with histocompatibility antigens thus far, (2) conditions that have an established hereditary or racial predisposition, and (3) those that have sporadic and unusual expressions or complications. It was clear in the discussion that emphasis should focus on populations from which maximal genetic information can be derived, i.e., family groups, sibships, or twinships. Twinships provide the opportunity to exclude environmental factors, whereas family groups and sibships provide an opportunity to demonstrate nonrandom segregation of HLA haplotypes in relation to infection. It was noted that there have been a number of populations developed for prospective epidemiologic surveys of families for infectious diseases that might be investigated further. Determination of HLA haplotypes of families in such studies would be relatively inexpensive, although the analysis of the relationships with various minor infections could be challenging. In addition, certain geographically restricted or closed population groups that have already been defined as to their histocompatibility patterns could be profitably employed for prospective studies of the relationship between HLA and infection. Finally, the Workshop recommended that future immunization studies for assay of new or prospective vaccines in both children and adults be conducted in family groups that can be HLA-typed. This would provide a unique op-
Downloaded from http://jid.oxfordjournals.org/ at Emory University on August 26, 2015
very nature inconclusive. It was agreed that the value of further studies of this kind would be very limited. Better developed case-control studies using carefully matched controls, especially where the controls include at least two siblings, are most appropriate for uncommon disorders such as rheumatic fever or Reye's syndrome. When practical by virtue of the prevalence of the disease, twin studies using monozygotic twins are especially useful when there is a need to discriminate between genetic and environmental factors in disease expression. The preferable type of study, whenever practicable, is the prospective study in which families or their appropriate members are used as the units of the cohort. Utilizing well-defined descriptors of the clinical and immunologic characteristics of the disorder along with HLA phenotype determination, such studies promise to yield the maximal amount of information with regard to the degree of association, the genetic contribution to the disorder in question, and the definition of nonrandom segregation of the disease with the genetic markers included for study. The alternative to this type of study would utilize individuals rather than families as the units for selection into the cohort. Such studies may be of less value since the information to be derived would concern associations between HLA and disease only without concomitant genetic information. By the same token, retrospective studies should recognize the unreliability of many of the determinants of both infection and immunity in episodes for which time of occurrence cannot be established.
Grayston and Payne
NIH News
249
portunity to assess various forms of immunologic responsiveness associated with histocompatibility genes.
J. THOMAS GRAYSTON Vice President for Health Affairs University of Washington Seattle) Washington FRED
J. PAYNE
1. Piazza, A., Belvedere, M. C., Bernoco, D., Conighi, C., Contu, L., Curtoni, E. S., Mattinz, P. L., Mayr, W.; Richiardi, P., Scudeller, G., Ceppellini, R. HL-A variation in four Sardinian villages under differential selective pressure by malaria. In Histocompatibility testing 1972. Munksgaard, Copenhagen, 1972, p. 73-84. 2. De Vries, R. R. P., Kreeftenberg, H. K., Loggen, H. G., van Rood, J. J. In vitro immune responsiveness to vaccinia virus and HLA. N. Eng!. J. Med. 297:692-696, 1977.
Downloaded from http://jid.oxfordjournals.org/ at Emory University on August 26, 2015
Research Epidemiologist Epidemiology and Biometry Branch Microbiology and Infectious Diseases Program National Institute of Allergy and Infectious Diseases National Institutes of Health
References
