▪ Abstract Twin and adoptee studies have indicated that host genetic factors are major determinants of susceptibility to infectious diseases in humans. Twin studies have also found high heritabilities for many humoral and cellular immune responses to pathogen antigens, with most of the genetic component mapping outside of the major histocompatibility complex. Candidate gene studies have implicated several immunogenetic polymorphisms in human infectious diseases. HLA variation has been associated with susceptibility or resistance to malaria, tuberculosis, leprosy, AIDS, and hepatitis virus persistence. Variation in the tumor necrosis factor gene promoter has also been associated with several infectious diseases. Chemokine receptor polymorphism affects both susceptibility to HIV-1 infection and the rate of progression to AIDS. Inactivating mutations of the γ-interferon receptor lead to increased susceptibility to atypical mycobacteria and disseminated BCG infection in homozygous children. The active form of...

The immunogenetics of human infectious diseases

Publisher Summary This chapter discusses the role of the immune response to Leishmania, with particular reference to the cutaneous disease caused by L. major. Leishmaniasis is caused by species of the intracellular protozoan parasite belonging to the genus Leishmania. There are three main categories of leishmaniasis: cutaneous leishmaniasis (oriental sore), mucocutaneous leishmaniasis (espundia), and visceral leishmaniasis (kala-azar). In humans, infection with Leishmania results in a spectrum of disease dependent upon the species involved and the efficiency of the host's immune response to the parasite. Diagnosis of active leishmaniasis is based primarily on the demonstration of the parasite in biopsies. A skin test using a killed whole parasite preparation (leishmanin) is used as a presumptive test. Genetic regulation of leishmaniasis is discussed in reference to mouse and humans, and the concept of suppressor T cells is reviewed. The various cytokines in leishmaniasis, including interferon (IFN) γ and interleukin (IL)-4, IL-10, IL-1, and IL-2 are also discussed.

Immunology of Leishmaniasis

Leishmaniases remain a major public health problem today despite the vast amount of research conducted on Leishmania pathogens. The biological model is genetically and ecologically complex. This paper explores the advances in Leishmania genetics and reviews population structure, taxonomy, epidemiology and pathogenicity. Current knowledge of Leishmania genetics is placed in the context of natural populations. Various studies have described a clonal structure for Leishmania but recombination, pseudo-recombination and other genetic processes have also been reported. The impact of these different models on epidemiology and the medical aspects of leishmaniases is considered from an evolutionary point of view. The role of these parasites in the expression of pathogenicity in humans is also explored. It is important to ascertain whether genetic variability of the parasites is related to the different clinical expressions of leishmaniasis. The review aims to put current knowledge of Leishmania and the leishmaniases in perspective and to underline priority questions which 'leishmaniacs' must answer in various domains: epidemiology, population genetics, taxonomy and pathogenicity. It concludes by presenting a number of feasible ways of responding to these questions.

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Leishmania and the leishmaniases: a parasite genetic update and advances in taxonomy, epidemiology and pathogenicity in humans.

Parasitic protozoa of the genus Leishmania have provided a useful perspective for immunologists in terms of host defense mechanisms critical for the resolution of infection caused by intracellular pathogens. These organisms, which normally reside in a late endosomal, major histocompatibility complex (MHC) class II(+) compartment within host macrophages cells, require CD4(+) T-cell responses for the control of disease. The paradigm for the CD4(+) T-helper 1 (Th1)/Th2 dichotomy is largely based on the curing/non-curing responses, respectively, to Leishmania major infection. However, this genus of parasitic protozoa is evolutionarily diverse, with the cutaneous disease-causing organisms of the Old World (L. major) and New World (Leishmania mexicana/ Leishmania amazonensis) having diverged 40-80 million years ago. Further adaptations to survive within the visceral organs (for Leishmania donovani, Leishmania chagasi, and Leishmania infantum) must have been required. Consequently, significant differences in host-parasite interactions have evolved. Different virulence factors have been identified for distinct Leishmania species, and there are profound differences in the immune mechanisms that mediate susceptibility/resistance to infection and in the pathology associated with disease. These variations not only point to interesting features of the host-pathogen interaction and immunobiology of this genus of parasitic protozoa, but also have important implications for immunotherapy and vaccine development.

Does the Leishmania major paradigm of pathogenesis and protection hold for New World cutaneous leishmaniases or the visceral disease

Immunopathogenesis of infection with the visceralizing Leishmania species.

Mapping of the locus controlling susceptibility to visceral leishmaniasis in the mouse.

Acute susceptibility of the mouse to Leishmania donovani is largely determined by a single locus designated Lsh Linkage between the Lsh locus and the Chromosome 1 marker Id-1 was detected using several sets of recombinant inbred strains Chromosome 1 linkage was confirmed in backcross generations using isoenzymes and a cytogenetic marker The data indicate that the gene order is centromere-Lsh-Id-1-ln-Dip-1 The estimated recombination frequency between Lsh and Id-1 is 012 +/- 004 This mapping is away from the known histocompatibility loci

D J Bradley

Papers

Mapping of the locus controlling susceptibility to visceral leishmaniasis in the mouse.

Regulation of Leishmania populations within the host. III. Mapping of the locus controlling susceptibility to visceral leishmaniasis in the mouse.