Genetics of susceptibility to leishmaniasis in mice: four novel loci and functional heterogeneity of gene effects.

Symptoms of human leishmaniasis range from subclinical to extensive systemic disease with splenomegaly, hepatomegaly, skin lesions, anemia and hyperglobulinemia, but the basis of this variation is unknown. Association of progression of the disease with Th2 lymphocyte response was reported in mice but not in humans. As most genetic studies in Leishmania major (L. major)-infected mice were restricted to skin lesions, we analyzed the symptomatology of leishmaniasis in mice by monitoring skin lesions, hepatomegaly, splenomegaly and seven immunological parameters. We detected and mapped 17 Leishmania major response (Lmr) gene loci that control the symptoms of infection. Surprisingly, the individual Lmr loci control 13 different combinations of pathological and immunological symptoms. Seven loci control both pathological and immunological parameters, 10 influence immunological parameters only. Moreover, the genetics of clinical symptoms is also very heterogeneous: loci Lmr13 and Lmr4 determine skin lesions only, Lmr5 and Lmr10 skin lesions and splenomegaly, Lmr14 and Lmr3 splenomegaly and hepatomegaly, Lmr3 (weakly) skin lesions, and Lmr15 hepatomegaly only. Only two immunological parameters, IgE and interferon-gamma serum levels, correlate partly with clinical manifestations. These findings extend the paradigm for the genetics of host response to infection to include numerous genes, each controlling a different set of organ-specific and systemic effects.

[Successful treatment of azoospermia diagnosed as "Sertoli cells only syndrome with maturation arrest"--developing a quality embryo]. / Uspesné resení azoospermie s diagnózou "Sertolli cells only syndrome" (SCO sy.) a Maturation Arrest (MA)--získání kvalitního embrya.

OBJECTIVE: The transfer of good quality embryo in the program of assisted reproduction in the case of azoospermia, dg. Sertolli cells only syndrome (SCO sy) + maturation arrest (MA). Testes were assessed and found to have a high occurrence of Sertolli cells and very low occurrence of germinal cells, which were arrested at the round spermatid level. The histological evaluation was hypospermatogenesis gr. 3 (minimum 1 spermatid/sample). DESIGN: Case report. SETTING: Laboratory IVF, Iscare, a. s., Department of Biology and Biochemistry of Fertilization, Institute of Molecular Genetics, Czech Academy of Sciences, Prague. SUBJECT AND METHOD: The successful integration of three methods provides a solution for this case of azoospermia. Immunology and histology can more exactly diagnose the degree of azoospermia. Detection and visualisation of spermatids using monoclonal antibodies against sperm proteins predicts the eventual occurrence of spermatogenesis, and histological evaluation confirms these immunological findings. Using the information of both methods it is possible to use special in vitro cultivation of testicular cells and so obtain injectable spermatozoa, or precursors of sperm, for the ICSI method. CONCLUSION: The probability of acquisition of good-quality embryo in the program of assisted reproduction is higher when these three methods are applied in combination.

Separation and mapping of multiple genes that control IgE level in Leishmania major infected mice.

The strain BALB/cHeA (BALB/c) is a high producer, and STS/A (STS) a low producer of IgE after Leishmania major infection. We analyzed this strain difference using 20 recombinant congenic (RC) BALB/c-c-STS/Dem (CcS/Dem) strains that carry different random subsets of 12.5% of genes of the strain STS on the BALB/c background. Strains CcS-16 and -20 exhibit a high and a low IgE level, respectively. In their F(2) hybrids with BALB/c we mapped nine Leishmania major response (Lmr) loci. Two of them we previously found to influence IgE level in CcS-5. IgE production in CcS-16 is controlled by loci on chromosomes 2, 10, 16 and 18 and in CcS-20 by loci on chromosomes 1, 3, 4, 5 and 8. The STS alleles of loci on chromosomes 1, 4, 5, 8 and 10 were associated with a low, whereas the STS alleles on chromosomes 16 and 18 with a high IgE production. The loci on chromosomes 2 and 3 have no apparent individual effect, but interact with the loci on chromosomes 10 and 1, respectively. The loci on chromosomes 10 and 18 were mapped in the regions homologous with the human regions containing genes that control total serum IgE and intensity of infection by Schistosoma mansoni, suggesting that some Lmr loci may participate in the pathways influencing atopic reactions and responses to several parasites. The definition of genes controlling anti-parasite responses will permit a better understanding of pathways and genetic diversity underlying the disease phenotypes.

Susceptibility to Leishmania major infection in mice: multiple loci and heterogeneity of immunopathological phenotypes.

Susceptibility as opposed to resistance of mouse strains (e.g., BALB/c vs C57BL/6) to Leishmania major has been attributed to a defective Th1 and a predominant Th2-response, resulting in increased IL-4 and IgE production, and decreased interferon gamma (IFN gamma) production, macrophage activation and elimination of parasites. Here we report dissection of genetic and functional aspects of susceptibility to leishmaniasis using two contrasting inbred strains BALB/cHeA (susceptible) and STS/A (resistant) and a resistant Recombinant Congenic (RC) Strain, CcS-5/Dem, which carries a random set of 12.5% of genes from the strain STS and 87.5% genes from the susceptible strain BALB/c. Linkage analysis of F2 hybrids between the resistant RC strain CcS-5 and the susceptible strain BALB/c revealed five loci affecting the response to the infection, each apparently associated with a different combination of pathological symptoms and immunological reactions. The correlation between Th2-type immune reactions and the disease in the F2 mice was either absent, or it was limited to mice with specific genotypes at loci on chromosomes 10 and 17. This suggests that the resistance vs susceptibility is influenced by mechanisms additional to the postulated antagonistic effects of Th1 and Th2 responses, and that the host's genotype affects the development of leishmaniasis in a complex way.

A new type of genetic regulation of allogeneic response. A novel locus on mouse chromosome 4, Alan2 controls MLC reactivity to three different alloantigens: C57BL/10, BALB/c and CBA.

The intensity of the mixed lymphocyte response (MLR) depends on the genetic disparity between the donors of responding and stimulating cells. Differences in the major histocompatibility complex (MHC) and Mls1 antigens induce the strongest responses. However, even with comparable incompatibilities in MHC and Mls antigens, some strains of genetically defined mice respond remarkably better than other strains. Apparently other, so far undefined, genetic factors contribute to the magnitude of the MLR. The strain OcB-9 (H2pz) has 87.5% genes from the strain O20/A (O20) and 12.5% genes from strain B10.O20 (both H2pz). In spite of the overal similarity of their genomes, OcB-9 mice differed from O20 mice in response to three different alloantigens C57BL/10 (H2b), BALB/c (H2d) and CBA (H2k). As both O20 and OcB-9 strains carry identical haplotype H2pz, their differences in alloantigen response depend only on non-MHC genes. We analyzed the genetic basis of these strain differences using (OcB-9 x O20)F2 hybrids, and we mapped a novel locus Alan2 (Alloantigen response 2) on chromosome 4 near D4Mit72 that influences the response to all alloantigens tested. This linkage was significant for C57BL/10 and for BALB/c alloantigens (corrected P values 0.0475 and 0.0158, respectively) and highly suggestive for CBA (corrected P = 0.0661). The response to DBA/1 (H2q) alloantigens exhibited a similar pattern but the linkage was not significant. As MLR reflects the recognition phase of transplantation reaction, identification of human counterparts of the Alan genes and a better understanding of the regulation of alloresponsiveness might lead to a better prediction of patients' reactions to allografts and to a more individualized measures to prevent rejection.