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 Emerging Infectious Diseases * Volume 3 * Number 1 * January-March 1997
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Synopses

Infectious Diseases and Immunity: Special Reference to Major
Histocompatibility Complex

Neeloo Singh,* S. Agrawal, and A.K. Rastogi*
*Department of Biochemistry, Central Drug Research Institute, Lucknow,
India; Department of Medical Genetics, Sanjay Gandhi Post Graduate
Institute of Medical Sciences, Lucknow, India
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      Human leukocyte antigens (HLAs) are an inherent system of
      alloantigens, which are the products of genes of the major
      histocompatibility complex (MHC). These genes span a region of
      approximately 4 centimorgans on the short arm of human
      chromosome 6 at band p 21.3 and encode the HLA class I and
      class II antigens, which play a central role in cell-to-cell
      interaction in the immune system. These antigens interact with
      the antigen-specific cell surface receptors of T lymphocytes
      (TCR) thus causing activation of the lymphocytes and the
      resulting immune response. Class I antigens restrict cytotoxic
      T-cell (CD8+) function thus killing viral infected targets,
      while class II antigens are involved in presentation of
      exogenous antigens to T-helper cells (CD4+) by antigen
      presenting cells (APC). The APC processes the antigens, and
      the immunogenic peptide is then presented at the cell surface
      along with the MHC molecule for recognition by the TCR. Since
      the MHC molecules play a central role in regulating the immune
      response, they may have an important role in controlling
      resistance and susceptibility to diseases. In this review we
      have highlighted studies conducted to look for an association
      between HLA and infectious diseases; such studies have had a
      variable degree of success because the pathogenesis of
      different diseases varies widely, and most diseases have a
      polygenic etiology.

Major Histocompatibility Complex (MHC) and Immune Response

Because of its remarkable power to deal with infection, the immune system
is central to the prevention and control of infectious disease. Immune
responsiveness is affected, even controlled, by gene products of the major
histocompatibility system (1). Many diseases are associated with human
leukocyte antigens (HLAs) (2,3). Moreover, in some infectious diseases
(4-6), the host immune reactivity, which is responsible for the pathologic
manifestation of disease, has been correlated with HLA specificities.

The discovery of the human MHC dates from the mid 1950s when
leukoagglutinating antibodies were found in the sera of patients who
received multiple transfusions and in the sera of 20% to 30% of multiparous
women. In humans, the entire histocompatibility complex is termed the HLA
complex. Genes coding for HLAs occupy a segment of approximately 4
centimorgans on the short arm of chromosome 6. The HLA-A, -B, and -C
genetic loci determine class I antigens; HLA-DR, -DP, -DQ genetic loci
determine class II antigens. Class I antigens are found on virtually every
human cell; class II antigens are found chiefly on the surfaces of
immunocompetent cells, including macrophages/monocytes, resting T
lymphocytes, activated T lymphocytes, and particularly B lymphocytes.

The MHC molecule provides a context for the recognition of antigens by T
lymphocytes. The polymorphic binding site of MHC class I and class II
molecules is composed of a -pleated sheet flanked by two alpha helixes.
They form a groove that accommodates one single microbial peptide ligand.

MHC class I molecules bind to peptides produced by the intracellular
degradation of viral proteins and display them on the cell surface for
recognition by CD8+ T lymphocytes. A class of white blood cells, the CD8 T
lymphocytes, bear receptors specific for the HLA class I antigens and route
pathogens such as viruses. Surface expression of class I MHC molecules
depends on the availability of peptides that bind MHC molecules in the
endoplasmic reticulum. A peptide transporter, associated with antigen
processing (TAP), plays an important role in maintaining adequate levels of
peptide (7). The transporter is a heterodimer encoded by two genes, TAP1
and TAP2, located in the MHC class II region. TAP genes belong to the
adenosine triphosphate (ATP) binding cassette super family of transport
proteins, which have two ATP-binding cassette domains and two transmembrane
domains. TAP genes are polymorphic (8), and allelic MHC differences may be
associated with disease by altering the peptides that bind class I MHC
molecules. Since human TAP genes are located between HLA-DP and HLA-DQ, TAP
alleles could result in an apparent disease association with class II HLA
alleles. Class I, i.e., HLA-A, -B, and -C molecules, play an important role
in viral infections in the lysis of target cells by cytotoxic killer T
lymphocytes.

MHC class II molecules are highly polymorphic membrane glycoproteins that
bind peptide fragments of proteins and display them for recognition by CD4+
T lymphocytes. The white blood cells known as CD4 T lymphocytes are of
central importance in defeating the bacteria and other parasites that live
within cells. The CD4 T lymphocytes are called helper T cells because they
secrete substances that amplify and control virtually all aspects of
immunity. These T cells have receptor molecules that can recognize one
particular peptide-HLA class II antigen combination. The binding capability
of any given peptide to MHC class II molecules depends on the primary
sequence of the peptide and allelic variation of the amino acid residues in
the binding site of the MHC receptor. Anchor residues defining
allele-specific peptide motifs have been identified in the class II binding
peptides. The proposed anchor residues combining with MHC pockets through
their side chains seem to be a primary requirement for peptide-MHC
interaction. The invariant chain (Ii) plays a critical role in the
assembly, intracellular transport, and function of MHC class II molecules
(9). In intracellular parasites (e.g., Leishmania infections of
macrophages), it is the class II MHC molecules that specifically bind to
receptors on these microbes.

HLA Association with Infectious Diseases

Infectious diseases are associated with impaired immunity. Some persons
mount very effective immune responses when given vaccines, while others
respond to vaccines poorly or not at all. The level of response is
determined by several factors: intensity of infection, factors related to
the intensity of the host immune response, T-cell state, T-cell function,
and perhaps most important, the genetic factor that interacts with the
other factors to determine the outcome of the disease. Infectious disease
research is now focusing on genetic markers such as allelic forms of HLA
molecules.

HLA Association with Mycobacterial Infections
Genetic factors may control host responses to Mycobacterium tuberculosis
(10-12). Several investigators have conducted population studies to
determine an association between pulmonary tuberculosis (TB) and HLA
specificities. HLA-DR2 is associated with the development of multibacillary
forms of both TB and leprosy (13,14); molecular subtyping of DR2 showed
that the majority of the allele in patients and controls was DRB1*1501 and
DRB1*1502. The frequency of these molecular subtypes of DR2 in patients was
not skewed, suggesting that the entire DR2 molecule or its closely linked
gene(s) may govern patient susceptibility to pulmonary TB and,
particularly, to drug-resistant TB. When the three-dimensional structure of
the HLA-DR molecule is elucidated (15), sequencing of class II alleles in
patients with pulmonary TB and drug-resistant TB could identify an amino
acid residue(s) critical for the binding of a M. tuberculosis-derived
pathogenic peptide(s) responsible for the detrimental or protective immune
response.

HLA alleles also modulate the immune response that determines the form of
leprosy (a heterogeneous disease caused by Mycobacterium leprae) that
develops in each patient (16,17). At one pole of the spectrum of leprosy
are the multibacillary lepromatous leprosy (LL) patients, who are anergic
to the antigens of M. leprae, and at the other extreme are the
paucibacillary tuberculoid leprosy (TT) patients, who exhibit a good
cell-mediated immune response. Humoral immunity is present throughout the
spectrum but does not seem to provide protection. Between the two poles are
patients with intermediate features as seen in the borderline lepromatous,
borderline leprosy (BB), and borderline tuberculoid forms (18). An
increased frequency of HLA-DR2 and -DQ1 in LL patients (19) and of HLA-DR3
in TT patients has been reported (20). These antigens can be further
subdivided into alleles defined by their amino acid sequence. A single
amino acid substitution may give rise to alleles with different immunologic
properties. The allele DRB1*1501 showed a stronger association with LL
patients than with TT patients (p < 0.00001). In addition, DQB1*0601 was
found significantly more often in LL patients than in controls (p <
0.00001); DQA1*0103 was more frequent in the LL group than in the
tuberculoid leprosy group; and DQA1*0102 was selectively increased in
patients with borderline lepromatous leprosy (Table 1). However, DRB1*0701,
DQB1*0201, and DQA1*0201 were decreased in LL patients compared with TT
patients and controls, and DQB1*0503 was selectively decreased in TT
patients, suggesting that these alleles might modulate the immune response
that determines the form of leprosy that develops in each patient (21).

              Table 1. Frequency of HLA class II alleles with
              significant differences between leprosy patients
              and healthy controls
              ------------------------------------------------
                          Healthy   Leprosy
                         controls  patients
                         --------------------
                 HLA       N=47      N=93
               alleles    N    %   N    %    RR(a)     p
              ------------------------------------------------
              DRB1*15    10 21.3   70 75.3  11.3   <0.00001
              DRB1*1501  6  12.8   49 52.7  7.6    <0.00001
              DRB1*1502  5  10.6   26 27.9  3.2    <0.05
              DRB5*0101  6  12.8   49 52.7  7.6    <0.00001
              DRB5*0102  5  10.6   26 27.9  3.2    <0.05
              DQA1*0102  9  19.1   38 40.9  2.9    <0.05
              DQA1*0103  13 27.6   48 51.6  2.8    <0.05
              DQB1*0601  8  17.0   56 60.2  7.4    <0.00001
              DRB1*0404  5  10.6   0  0.0   0.04   <0.01
              DRB1*0701  13 29.8   11 11.8  0.3    <0.05
              DRB1*1401  4  8.5    0  0.0   0.005  <0.05
              DQB1*0503  16 36.2   14 16.1  0.3    <0.05
              ------------------------------------------------
              (a)RR = relative risk

HLA Association with Parasitic Infections
Because there are significant differences between malaria-exposed and
-unexposed populations in the frequencies of HLA genes at the A and B loci,
the HLA complex may protect populations in endemic-disease areas who are
exposed to malaria parasites. The adaptative mechanisms may be expressed by
HLA-associated genes that control immune responsiveness to malaria
antigens. The association between the HLA class I antigen HLA-B53 and
protection from severe malaria has been well established (5). This link
might be mediated by HLA class I restricted cytotoxic T lymphocytes (CTL)
during the liver stage of the parasite's life cycle (22). The protective
association between HLA-B53 and severe malaria was investigated by
sequencing peptides eluted from this molecule before testing candidate
epitopes from preerythrocytic-stage antigens of Plasmodium falciparum in
biochemical and cellular assays. Among malaria-immune Africans, HLA-B53
restricted CTL recognized a conserved nonamerpeptide from liver
stage-specific antigen, but no HLA-B53 restricted epitopes were identified
in antigens from other stages (5). These findings indicate a possible
molecular basis for this HLA disease association and support the candidacy
of liver stage-specific antigen as a malaria vaccine component.

The association between HLA-DR/-DQ phenotypes and immune response to
circumsporozoite protein of the human malaria parasite were investigated in
Thai adults (23). Evidence suggests that human T- and B-cell responses to a
major P. falciparum antigen (Pf RESA) in persons primed by repeated
infections are genetically regulated (24). To associate T-cell and antibody
responses with the donors' MHC class II genotypes, genomic HLA class II
typing of DQ antigens of leukocytes from 145 donors living in
endemic-disease regions of Africa were performed by restriction fragment
length polymorphism (24). These data imply that the impact of MHC class II
gene products on specific immune responses to Pf 155/ RESA epitopes is weak
and hard to demonstrate in outbred human populations naturally primed by
infection. The relationship between class II HLA and immune recognition of
three candidate antigens for a vaccine against P. falciparum was
investigated in persons extremely heterozygous for HLA class II alleles
living in an endemic-disease area of West Africa (25). One class II DQA-DQB
combination (serologic specificity DQw2) was particularly common among
these persons. This haplotype was significantly associated with higher than
average levels of antibody to a peptide epitope (EENV)6 of Pf RESA. There
was little evidence of association between HLA class II genotype and
cellular proliferation responses to the antigen tested.

The frequency of HLAs was studied in 62 patients with scabies and 27
patients with cutaneous leishmaniasis to evaluate the role of HLA antigens
as genetic markers in the pathogenesis of these parasitic skin diseases. A
significant statistical association was found between HLA-A11 antigen and
scabies and between HLA-A11, -B5, and -B7 antigens and diffuse cutaneous
leishmaniasis (26). In another study, 24 families with one or more cases of
localized cutaneous leishmaniasis from an endemic-disease region with the
highest incidence of localized cutaneous leishmaniasis in Venezuela were
typed for HLA-A, -B, -C, -DR, and -DQ antigens and complement factors. The
parental HLA haplotypes segregated at random among healthy and affected
siblings, but in backcross families significantly higher frequencies of
HLA-A28, -Bw22 or -DQw8 were present in infected compared with healthy
siblings (27). In addition, HLA-B15 showed a higher frequency among healthy
siblings. Haplotypes Bw22, DR11, DQw7 were also significantly more frequent
in infected than in healthy siblings. No HLA linkage with a putative
localized cutaneous leishmaniasis susceptibility gene(s) could be
demonstrated in this study (27). A case/control comparison of 26 unrelated
localized cutaneous leishmaniasis patients and healthy persons of the same
ethnic origin confirmed the association of HLA-Bw22 and DQw3 with this
disease. The relative risk reached 12.5 for Bw22 and 4.55 for DQw3.
HLA-DQw3 apparently makes the major contribution as a genetic risk factor
for localized cutaneous leishmaniasis at the population level. In another
study, a statistically significant association was found between HLA-B5 and
-DR3 and schistosomiasis (28).

A study of the association of HLA class I antigen frequencies in 52
patients with kala-azar and 222 unrelated healthy controls in Iran found
HLA-A26 to be statistically significant (p = 0.004) (29). This indicates a
high risk of contracting the disease for HLA-A26 positive persons and a
remarkable influence of this antigen on the prevalence rate of kala-azar.

The significance of susceptibility/protection correlations between HLA and
parasitic diseases has been established by serologic typing methods. To
improve the accuracy of MHC-disease associations, we have used a DNA-based
HLA typing method, namely polymerase chain reaction with sequence specific
oligonucleotide probes, for the molecular typing of kala-azar patients in
India (30). To study the possible association at the molecular level of HLA
class I (A and B) as well as class II (DR) antigens in kala-azar patients,
we typed patients with kala-azar by polymerase chain reaction with sequence
specific oligonucleotide probes and compared the antigen frequencies with
healthy family-based controls. On the basis of the distribution of alleles
in each sample, percentage phenotype and genotype frequencies were
calculated for both control and kala-azar patients. Statistical analysis
using the Transmission Disequilibrium Test was carried out to assess the
association of different HLA allelic specificities with kala-azar patients.
No significant association between any of the HLA class I or class II
antigens was found. We will conduct a linkage analysis study based on the
data from typing the above-mentioned case/controls. The findings might lead
to a new dimension in the study of HLA association with parasitic
infections: genetic markers, such as HLA, that are sufficiently polymorphic
(as measured by their heterozygosities) can be used in linkage and
association analysis to detect Mendelian segregation underlying disease
phenotypes (31).

Comprehensive analysis of HLA associations with infectious diseases has
allowed precise definition of susceptibility and protective alleles in
large populations of different ethnic origins. Of great interest in the
fine dissection of molecular mechanisms leading to parasitic diseases,
these studies also provide the genetic basis for identification of the
subset of persons at risk for subsequent infection. Infectious diseases may
have exerted significant pressure on the development and maintenance of HLA
polymorphism (32). Widespread and frequently fatal parasitic diseases such
as malaria have selectively maintained certain gene frequencies in
endemic-disease areas (33).

Although HLA associations with parasitic diseases have provided clues to
pathogenesis, the molecular basis of these associations has not yet been
defined. The determinant selection hypothesis, which states that
associations result from the ability of a particular HLA type to present a
critical antigenic peptide, has been difficult to investigate because, for
most disease associations, the relevant antigen is unknown. Recently, the
identification of characteristic sequence features in peptides eluted from
HLA class I molecules (34,35) suggested that the relevant antigen might be
identifiable by assessing cellular immune responses to peptides containing
such motifs among antigens that are candidates for mediating HLA disease
associations. With the development of modern techniques of the HLA assembly
assay (36), relevant peptides can be synthesized; it can then be determined
whether they have any function as CTL epitopes during immune responses.
Such studies will elucidate the HLA associations with parasitic infections
and the molecular basis of these associations and facilitate the
development of vaccines for these infectious diseases.

HLA Association with Viral Infections
The associations of viral diseases with HLA alleles have not been studied
extensively. However, mechanisms by which HLA molecules determine the
immune response to viral peptides have been well studied as part of efforts
to develop safe and efficient virus vaccines. Successful development of
vaccines against viral infections depends on the ability of inactivated and
live virus vaccines to induce a humoral immune response and produce
antiviral neutralization antibodies. Additionally, virus vaccines that
induce a cellular immune response leading to the destruction of
virus-infected cells by CD8+ CTLs may be needed to provide protection
against some viral infections. Antiviral CD8+ CTLs are induced by viral
peptides presented within the peptide binding grooves of HLA class I
molecules on the surface of infected cells. Studies in the last decade have
provided an insight into the presentation of viral peptides by HLA class I
molecules to CD8+ T cells.

Herpesvirus saimiri, an oncogenic, lymphotropic, gamma-herpesvirus,
transforms human and simian T cells in vitro and causes lymphomas and
leukemias in various species of New World primates. An open reading frame
of the H. saimiri genome encodes a heavily glycosylated protein that is
secreted and binds to heterodimeric MHC class II HLA-DR molecules (37).
These results indicate that the open reading frame can function as an
immunomodulator that may contribute to the immunopathology of H. saimiri
infection.

Cytotoxic T cells that recognize dengue virus peptides have been reported
(38). Analysis of HLA class I haplotype-restricted peptides showed that
HLA-A2 and -A68 motifs were abundant compared with nonpeptides with
HLA-A24, -B8, and -B53 motifs. Studies by Zeng et al. (39) suggest that the
T-cell response to dengue virus is restricted by the HLA-DR15 allele.
Becker (40) developed an approach to priming antiviral CD8+ CTLs that may
provide cellular immune protection from flavivirus infection without
inducing the humoral immune response associated with dengue fever shock
syndrome. He proposed using synthetic flavivirus peptides with an amino
acid motif to fit with the HLA class I peptide binding group of HLA
haplotypes prevalent in a given population in an endemic-disease area as an
immunogen. These synthetic viral peptides may be introduced into the human
skin by using a lotion containing the peptides (Peplotion) and substances
capable of enhancing the penetration of these peptides into the skin to
reach Langerhans cells. The peptide-treated Langerhans cells, professional
antigen presenting cells, may bind the synthetic viral peptides by their
HLA class I peptide binding grooves. Antigens carrying Langerhans cells can
migrate and induce the cellular immune response in the lymph nodes.

Transmission of human immunodeficiency virus 1 (HIV-1) from an infected
woman to her offspring during gestation and delivery is influenced by the
infant's MHC class II DRB1 alleles. Forty-six HIV-infected infants and 63
seroreverting infants, born with passively acquired anti-HIV antibodies but
not becoming detectably infected, were typed by an automated
nucleotide-sequence-based technique (41). One or more DR-13 alleles,
including DRB1*1301, 1302, and 1303 were found in 15.2% of those becoming
HIV-infected and 31.7% of seroreverting infants (p = 0.048); this
association was influenced by ethnicity. Upon examining for other allelic
associations, only the DR2 allele DRB1*1501 was associated with
seroreversion in Caucasian infants. Among these infants, the DRB1*03011
allele was positively associated with HIV infection.

Molecular mimicry, where structural properties borne by a pathogen
"imitate" or "simulate" molecules of the host, also appears to be an
important mechanism in the association of HLA molecules with viral disease.
Molecular mimicry takes different forms in the molecular biology of HIV-1
(42). Molecular mimicry between HIV envelope proteins and HLA class II
molecules may lead to autoimmunity against CD4+ T cell expressing class II
molecules (43). Bisset (44) states that both the HIV-1 gp 120 envelope and
Mycoplasma genitalium adhesion proteins share an area of significant
similarity with the CD4-binding site of the class II MHC proteins.
Interaction with this triad could contribute to T-cell dysfunction, T-cell
depletion, Th1-cell-Th2-cell shift, B-cell proliferation,
hyperglobulinemia, and antigen-presenting cell dysfunction.

HLA-DR has been evaluated as a marker for immune response related to human
cytomegalovirus infection (45); this virus plays a role in chronic
inflammatory reaction in inflammatory abdominal aortic aneurysm. In the
fibrously thickened adventitia of this aneurysm, human
cytomegalovirus-infected cells and HLA-DR positive cells were more
frequently encountered than in that of atherosclerotic aneurysms and
control cases (p < 0.01).

An estimated 250 million people throughout the world are chronically
infected with hepatitis B virus, the primary cause of chronic hepatitis,
cirrhosis, and hepatocellular carcinoma in endemic-disease areas (46,47).
Because HLA class I antigens contain viral peptides, they may be important
targets for immune mediated hepatocytolysis by CD8+ CTLs in hepatitis B
virus infection (48). Davenport et al. (49) have shown that HLA-DR13 is
associated with resistance to hepatitis B virus infection. Prognosis may be
quite different among patients infected with hepatitis C virus: a chronic
liver disease occurs in half the patients, while the other half exhibits no
signs of histologic progression of liver damage. The host immune responses
may play an important role in such different outcomes. To identify human
CTL epitopes in the NS3 region of hepatitis C virus, Kurokohchi et al. (50)
modified an approach using recombinant protein and the ability of short
peptides to bind to class I MHC molecules. They identified a cytotoxic
T-cell epitope presented by HLA-A2 in the hepatitis C virus NS3 region. A
study conducted by Peano et al. (51) establishes that HLA-DR5 antigen
appears as a protective factor against a severe outcome of hepatitis C
virus infection.

Epstein-Barr virus, a member of the herpesvirus family, has been associated
with virus replication (infectious mononucleosis, oral hairy leukoplakia)
as well as neoplastic conditions such as nasopharyngeal carcinoma, B-cell
lymphoma, and Hodgkin disease associated with viral latency. An influence
of CTL response on Epstein-Barr virus evolution was first suggested by the
finding that virus isolates from highly HLA-A11-positive Asian populations
were specifically mutated in two immunodominant A11 restricted CTL epitopes
(52). Additionally, B35.01-restricted CTL responses in white donors
reproducibly map to a single peptide epitope (53). However, most
Epstein-Barr virus isolates from a population where B35.01 was prevalent
(in the Gambia) either retained the CTL epitope sequence or carried a
mutation that conserved antigenicity; changes leading to reduced
antigenicity were found in only a minority of cases. Two epitopes for
Epstein-Barr virus specific CTLs restricted by the common allele HLA-B7
were identified by Hill et al. (54).

The level of serum HLA class I antigens markedly increases during the
course of viral infections such as those caused by cytomegalovirus,
hepatitis B virus, hepatitis C virus, HIV-1, and varicella-zoster virus
(55-57). During HIV-1 infection, the level of serum HLA class I antigens
correlates with disease stage and represents a good prognostic marker of
disease progression (55).

HLA Association with Bacterial Infections
Vaccines based on recombinant attenuated bacteria represent a potentially
safe and effective immunization strategy. A carrier system was developed by
Verjans et al. (58) to analyze in vitro whether foreign T-cell epitopes,
inserted in the outer membrane protein PhoE of Escherichia coli and
expressed by recombinant bacteria, are efficiently processed and presented
through HLA class I and II molecules by infected human macrophages.

A well-defined HLA-B27 restricted cytotoxic T-cell epitope and an HLA-DR53
restricted T-helper epitope of the fusion protein of measles virus were
genetically inserted in a surface-exposed region of PhoE, and the chimeric
proteins were expressed in E. coli and Salmonella typhimurium. Macrophages
infected with recombinant bacteria presented the T-helper epitope to a
specific CD4+ T-cell clone but failed to present the CTL epitope to the
specific CD8+ T-cell clone. Phagocytic processing of intact bacteria within
infected macrophages was essential for antigen presentation by HLA class
II. Nascent HLA class II molecules were also required for the presentation
of the T-helper epitope to the CD4+ T-cell clone by infected macrophages.

HLA associations may also link various diseases; for example the HLA-B27
association for ankylosing spondylitis, Reiter disease, reactive
arthropathy, and acute anterior uveitis indicate that these disorders may
share a pathogenic pathway. According to the molecular mimicry hypothesis,
antigens carried by a particular pathogen may resemble a certain HLA
allomorph. As the person carrying this allomorph is unresponsive to it, it
is susceptible to the disease caused by the pathogen. For example, some
investigators believe that one of the antigens of Klebsiella resembles
HLA-B27 and that pathogen is responsible for ankylosing spondylitis (59).
In most patients who have an acute attack of anterior uveitis, a common
ocular disease characterized by inflammation of the iris and ciliary body,
the only clues to the pathogenesis of this disease are its close
association with the genetic marker HLA-B27 and the likely triggering role
of a variety of gram-negative bacteria (60). HLA-B27 acute anterior uveitis
appears to be a distinct clinical entity frequently associated with the
seronegative arthropathies, such as ankylosing spondylitis and Reiter
syndrome.

Sasazuki (61) showed that low responsiveness to streptococcal cell wall
antigen was inherited as an HLA-linked dominant trait. The immune
suppression gene for streptococcal cell wall was in strong linkage
disequilibrium with particular alleles of the HLA-DQ locus. This shows that
the HLA-linked immune suppression genes exist in humans to control low
response to natural antigens.

Table 2 lists the associations that have been established between various
HLA factors and certain infectious diseases. Only the antigens showing
statistically significant associations are indicated. Because some persons
are unresponsive to certain critical epitopes of the pathogens presumably
responsible for certain infectious diseases, particular HLA alleles occur
more frequently in patients with certain infectious diseases than in
healthy persons; therefore, researchers associate these diseases with
certain HLA alleles. This article has summarized the findings from
population genetic analysis and from studies of the association of immune
response mechanisms of infectious diseases and HLA.

            Table 2. Association between human leukocyte
            antigen (HLA) and some infectious diseases
            ----------------------------------------------------
                                          HLA
            Disease                       Association
            ----------------------------------------------------

            Bacterial
            ---------
            Ankylosing spondylitis        B27
            Reiter disease                B27
            Acute anterior uveitis        B7

            Mycobacterial
            -------------
            Tuberculosis and leprosy      DR2
                (multibacillary forms)    (DRB1*1501, 1502)
                lepromatous leprosy       DR2 and DQ1
                paucibacillary
            tuberculoid                   DR3

            Viral
            -----
            Dengue fever virus            DR15
            Human immunodeficiency        DR13
                virus 1                   (DRB1*1301, 1302,
                                          1303)
                                          DR2
                                          (DRB1*1501)
                                          DRB1*03011
            Hepatitis B virus             DR13
            Hepatitis C virus             A2
                                          DR5
            Epstein-Barr virus            B35.01
                                          A11
                                          B7

            Parasitic
            ---------
            Malaria                       B53
            Scabies                       A11
            Diffuse cutaneous             A11, B5, B7
                leishmaniasis
            Localized cutaneous           A28, Bw22, DQw8
                leishmaniasis             Bw22, DR11, Qw7
                                          Bw22, Dqw3
            Schistosomiasis               B5, DR3
            Visceral leishmaniasis        A26
            ----------------------------------------------------

      Acknowledgments

      We are grateful to Dr. Derek Middleton for critically reading
      the manuscript and Dr. Martin Curran and Mr. J.C. Sharma for
      their help in the literature survey. This work was supported by
      a grant from the Department of Science and Technology, India
      (No. SR/OY/MB-10/92).

Dr. Singh is a scientist in the Department of Biochemistry, Central Drug
Research Institute, Lucknow. Her research interest is visceral
leishmaniasis, or kala-azar, as it is known in eastern India, where the
disease is now epidemic. She is developing PCR-based diagnostics for the
disease focusing on kinetoplast DNA, studying the molecular mechanisms of
drug resistance, and striving to answer the most important question: are
host genetic factors, like HLA, involved in susceptibility to kala-azar in
India.

Address for Correspondence: Neeloo Singh, Department of Biochemistry,
Central Drug Research Institute, Lucknow, India;fax: 91-522-223-405;
e-mail: root@cscdri.ren.nic.in.

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Emerging Infectious Diseases
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