Immune response gene regulation of the humoral immune response to Porphyromonas gingivalis fimbriae in mice.

Among various strains of mice immunized orally with Porphyromonas gingivalis fimbriae and adjuvant GM-53 in liposomes, BALB/c and DBA/2 mice (H-2d) were found to be high responders to the fimbriae, CBA/J and C3H mice (H-2k) were intermediate, while C57BL/6 mice were low responders in terms of serum IgG and salivary IgA responses. Furthermore, humoral immune responses were examined using congeneic mice of B10 background showing different H-2 haplotypes, and it was revealed that B10.D2 mice (H-2d), followed by B10.BR (H-2k), responded well to antigenic stimulation of the fimbriae, while C57BL/10 mice (B10, H-2b) were low responders to the fimbriae. Hybrids between BALB/c and C57BL/6 mice were found to reflect a phenotype of low responders. Thus, the humoral immune responses to P. gingivalis in mice are restricted by H-2 haplotype.     

CD40L is critical for protection from demyelinating disease and development of spontaneous remyelination in a mouse model of multiple sclerosis

Theiler's murine encephalomyelitis virus (TMEV) induces acute neuronal disease followed by chronic demyelination in susceptible strains of mice. In this study we examined the role of a limited immune defect (deletion or blocking of CD40 ligand [CD40L]) on the extent of brain disease, susceptibility to demyelination, and the ability of demyelinated mice to spontaneously remyelinate following TMEV infection. We demonstrated that CD40L-dependent immune responses participate in pathogenesis in the cerebellum and the spinal cord white matter but protect the striatum of susceptible SJL/J mice. In mice on a background resistant to TMEV-induced demyelination (C57BL/6), the lack of CD40L resulted in increased striatal disease and meningeal inflammation. In addition, CD40L was required to maintain resistance to demyelination and clinical deficits in H-2 ^b mice. CD40L-mediated interactions were also necessary for development of protective H-2^b-restricted cytotoxic T cell responses directed against the VP2 region of TMEV as well as for spontaneous remyelination of the spinal cord white matter. The data presented here demonstrated the critical role of this molecule in both antibody- and cell-mediated protective immune responses in distinct phases of TMEV-mediated pathology.     

Protective immunity in toxoplasmosis: correlation between antibody response, brain cyst formation, T-cell activation, and survival in normal and B-cell-deficient mice bearing the H-2k haplotype.

Correlations of Toxoplasma gondii-specific immunoglobulin M (IgM) and IgG production, antigen-specific T-cell activation, and the number of brain cysts were compared in immunocompetent CBA/J (H-2k), C3H/He (H-2k), and B-cell-deficient CBA/N (H-2k) mice. Almost all of the C3H/He mice (94%) survived in comparison to CBA/J (71%) and CBA/N (53%) mice following infection with 20 cysts of Me 49, an avirulent strain of T. gondii. The mortality in susceptible mice was reduced by treatment of the animals with sulfadiazine during the acute stage of infection. Decreased mortality in CBA/J and C3H/He mice as well as in B-cell-deficient mice was paralleled by formation of fewer brain cysts. The Toxoplasma-specific T-cell proliferation was markedly enhanced in all three strains at day 15 postinfection but not at day 45 postinfection when compared to animals not treated with the drug. In contrast, Toxoplasma-specific IgM and IgG levels were lower in CBA/J and CBA/N mice treated with sulfadiazine than in untreated mice of these strains. Although CBA/N mice developed almost no humoral response either with or without drug treatment, they produced fewer brain cysts than normal CBA/J mice. The results indicate a major role of cell-mediated immunity in protection against an acute Toxoplasma infection.     

Role of T cells in resistance to Theiler's virus infection.

Intracerebral infection of C57BL/10SNJ mice with Theiler's virus results in acute encephalitis with subsequent virus clearance and absence of spinal cord demyelination. In contrast, infection of SJL/J mice results in acute encephalitis, virus persistence, and immune-mediated demyelination. These experiments examined the role of T-cell subsets in the in vivo immune response to Theiler's virus in resistant C57BL/10SNJ mice. Depletion of T-cell subsets with monoclonal antibodies (mAbs) directed at CD3 (pan-T-cell marker), CD4+ (class II-restricted) or CD8+ (class I-restricted) T cells resulted in increased frequency of paralysis and death as a result of acute encephalitis. Neuropathologic studies 10 days after infection demonstrated prominent necrosis, primarily in the pyramidal layer of hippocampus and in the thalamus of mice depleted of T-cell subsets. In immunosuppressed and infected C57BL/10SNJ mice, analysis of spinal cord sections 35 days after infection demonstrated small demyelinated lesions relatively devoid of inflammatory cells even though virus antigen could be detected by immunocytochemistry. Both CD4+ and CD8+ T cells are important in the resistance to infection with Theiler's virus in C57BL/10SNJ mice. However, subsequent spinal cord demyelination, to the extent observed in susceptible mice, depends on the presence of virus antigen persistence and a competent cellular immune response.     

B1 cells contribution to susceptibility in experimental paracoccidioidomycosis: immunoglobulin isotypes and repertoire determination.

Paracoccidioidomycosis (PCM) is the most prevalent systemic mycosis in Latin America. The experimental murine model has been used to approach the disease, with susceptible and resistant mice strains that reproduce most of the main human immunological features. Since the hypergammaglobulinemia observed in susceptible mice and humans might have an influence on B1 cells, we investigated its role during the experimental infection with Paracoccidiodes brasiliensis. CBA/Nxid mice, deficient in B1 cells, and CBA/Nxid reconstituted with B1 cells isolated from the non-mutant CBA/J strain were infected with 106 yeast forms of P. brasiliensis. At the 8th and 22nd week post infection the DTH response of CBA/Nxid mice was significantly higher after 24 h of P. brasiliensis antigens inoculation and the specific humoral response was reduced, in comparison to CBA/J or recCBA/Nxid. Production of NAbs is a hallmark of the B1 subset. Higher Ig productions to auto antigens such as DNA, MBP and RBC were observed in CBA/J infected mice or recCBA/Nxid. Anti P. brasiliensis IgG2a was produced by CBA/Nxid mice early in infection, while CBA/J or recCBA/Nxid presented increased levels of this isotype only after the 8th week of infection. Furthermore, western blotting analysis showed that CBA/Nxid mice expanded less clones against P. brasiliensis antigens, with weakly detectable anti-gp43 antibodies while CBA/J mice produce IgM anti-gp43 at the 2nd week of infection and IgG anti-gp43 at the 2nd and 8th week. On the other hand, recognition of gp70, a fungal antigen that, as gp43, inhibits macrophage activation was not compromised in B1 deficient mice. These results suggest that B1 cells might have influence in the kinetic of production of protective isotypes of immunoglobulins and their repertoire that could contribute to an early drive towards a Th2 response, affecting the cellular response in susceptible mice during experimental paracoccidiodomycosis.     

Experimental autoimmune thyroiditis (EAT) induced by the thyroglobulin peptide (2596-2608): influence of H-2 and non H-2 genes

We have previously identified five thyroglobulin (Tg) peptides with Ak-binding motifs that induce experimental autoimmune thyroiditis (EAT) in CBA/J (H-2k) mice. In this study, we have examined whether H-2 or non H-2 genes can influence the immunopathogenicity of peptide p2596 (a.a. 2596-2608), which earlier elicited considerable pathology in CBA/J hosts. The p2596 peptide induced mild EAT--(infiltration index range=1-2)-- in H-2-compatible AKR/J, B10.BR, and C3H/HeJ mice. Moreover, p2596-primed LNC from these mice exhibited peptide-specific proliferative responses and secreted significant amounts of IL-2 and IFN-gamma in recall in vitro assays. Priming and boosting of these strains with p2596 resulted in the generation of specific IgG responses five weeks after the initial challenge. In contrast, s.c. challenge of H-2-incompatible strains such as DBA/1J (H-2q), SJL (H-2s), DBA/2J (H-2d) and C57BL/6 (H-2b) with the same peptide dose did not elicit EAT pathology and peptide-specific B- or T-cell responses. These data demonstrate the thyroiditogenic potential of p2596 in H-2k strains of diverse non-H-2 backgrounds but not in mice carrying H-2b, d, q or s haplotypes.     

Chronic giardiasis in B-cell-deficient mice expressing the xid gene.

The role of antibody in immunity to Giardia muris infection was investigated by studying B-cell-deficient CBA/N mice expressing the xid gene. After gastric administration of infective G. muris cysts, CBA/N male and female mice developed prolonged G. muris infection, whereas BALB/c mice eliminated their infection in 6 to 8 weeks. Male F1 progeny obtained from matings between female CBA/N mice and male BALB/c mice expressed the xid gene and developed prolonged infections. In contrast, all other F1 progeny of CBA/N and BALB/c matings, which did express the xid gene, eliminated G. muris. The link between the xid gene and prolonged infection was confirmed by studies of C57BL/6 mice congenic for the xid gene. When compared with BALB/c or F1 mice, CBA/N mice produced large quantities of immunoglobulin A (IgA) anti-G. muris antibody in serum and gut secretions during prolonged infection. Serum IgG anti-G. muris antibody levels were reduced in CBA/N and F1 male mice that expressed the xid gene. The inability of xid mice to eliminate G. muris is consistent with the importance of antibody in the development of immunity to G. muris. We hypothesize that mice bearing the xid gene fail to produce IgA antibody of appropriate specificity to an antigen or antigens whose recognition by antibody is critical for successful elimination of the parasite.     

Pathogenicity of a human thyroglobulin peptide (2340-2359) in mice with high or low genetic susceptibility to thyroiditis

We have previously identified a 20-mer peptide of human thyroglobulin (hTg), p2340 (aa2340-2359), which induced experimental autoimmune thyroiditis (EAT) in AKR/J (H-2(k)) and HLA-DR3 transgenic mice. In this study, we investigated the thyroiditogenic potential of p2340 in 'high responder' CBA/J (H-2(k)) and SJL/J (H-2(s)) or 'low responder' C57BL/6 (H-2(b)) and BALB/c (H-2(d)) mice. Mice were immunized subcutaneously with 100 nmol of p2340 in complete Freund's adjuvant (CFA) and both the proliferative capacity of their lymph node cells in the presence of p2340 or intact Tg and the production of peptide-specific antibodies were investigated. The p2340 peptide was found to contain B-cell and non-dominant T-cell epitope(s) in all strains tested. Moreover, it elicited EAT in CBA/J (2/6, infiltration index (I.I.) 1) and SJL/J (5/5, I.I. 1-3) mice after direct challenge and in BALB/c (4/7, I.I. 1) and C57BL/6 (1/5, I.I. 1) after adoptive transfer of p2340-primed lymph node cells. P2340 is the first Tg peptide found to be pathogenic in low as well as high responder mouse strains and thus will allow us to investigate mechanisms of EAT induction in a genetically resistant host.     

Correlation between levels of immunoglobulins and immune complexes in plasma of C57BL/6 and C57L/J mice infected with MAIDS retrovirus.

Infection with helper-free, defective MAIDS murine leukemia virus (MuLV) caused a rapid polyclonal activation of B cells in 0.75-, 2-, and 6-month-old C57L/J mice (H-2b, Fv-1n/n), similar to that in C57BL/6 mice (H-2b, Fv-1b/b), which was recognized by elevated plasma immunoglobulin concentrations. However, changes in plasma immunoglobulin levels differed in C57BL/J and C57BL/6 mice. In C57L/J mice, infection resulted in a rapid increase in plasma IgM and IgG2a, and the elevation of IgG2a persisted undiminished for 21 weeks. Levels of IgG2b also became slightly elevated, but those of IgG1 and IgG3 were not significantly affected. Plasma of 6 to 7-month-old C57BL/6 mice contained already high levels of IgM (30-40 mg/ml), which persisted undiminished in uninfected mice but decreased progressively in infected mice to 10% of the original concentration during 25 weeks of observation. In C57BL/6 mice, plasma IgG1 and IgG2b as well as IgG2a became similarly elevated after infection but also only transiently. Their levels began to decrease progressively about 10 weeks after infection and fell to far below the maximum concentration observed. The drastic loss of plasma IgM and IgGs observed in C57BL/6 mice during the later stages of MAIDS MuLV infection did not seem to be a consequence of the polyclonal activation of B cells per se but seemed to reflect additional immunological abnormalities arising in infected C57BL/6 but not C57L/J mice. In both mouse strains these changes in plasma Ig levels correlated with the formation of Ig-containing immune complexes that bound to high-affinity, protein-binding ELISA plates in the absence of antigen coating, which may represent unusual forms of self-antigen-antibody complexes.     

Resistance and susceptibility of mice to bacterial infection: genetics of listeriosis.

A survey of various strains of mice showed distinct differences in resistance or susceptibility to Listeria monocytogenes. C57B1, related sublines, NZB, and SJL were resistant to Listeria, whereas BALB/c, CBA, A, DBA/1, C3H, LP.RIII, 129, and WB were susceptible. The gene(s) responsible for resistance and susceptibility to Listeria were studied in detail. C57BL6/6, B10.D2, and B10.A mice were 100 times more resistant than were BALB/c, CBA, and A. Resistance of the (C57B1/6 X BALB/C)F1 was intermediate between the two parents, suggesting partial penetration of a dominant gene. Backcross studies in which the (C57B1/6 X BALB/c)F1 were crossed with the susceptible BALB/c parent suggested that a single gene or group of linked genes were the major determinant of resistance, although the possibility that other genes exerted a modifying influence was not excluded. By using the backcross and various congenic and recombinant mice, linkage of the genes involved to the H-1, H-2, H-3, H-4, H-7, or H-8 loci, to the immunoglobulin allotype, to the Thy-1 gene, to the Hc gene specifying C5, or to coat color genes (B, c) was excluded. There was no difference in the response of males and females. In all studies, the powerful overriding influence of the C57B1 genome was evident.     

Role of the H-2s haplotype in survival of mice after infection with Trypanosoma cruzi.

In studies of the resistance of inbred mice to infection with Trypanosoma cruzi Peru, mouse strain B10.S was the only strain which survived the infection resulting from the inoculation of 10(3) trypomastigotes. This is the only inbred mouse strain studied to survive infection. To investigate the effect of the H-2 haplotype on survival, C57BL/10 congenic mouse strains bearing H-2S recombinant haplotypes and mouse strains A.SWSn/J and SJL/J were tested for their ability to overcome the T. cruzi infection. None of the recombinant strains tested, including B10.S(7R), B10.S(8R), B10.S(9R), and B10.HTT, survived the infection, indicating that at least two or more regions of the H-2 locus must be H-2S to ensure survival. Strains A.SWSn/J and SJL/J with the H-2S haplotype did not survive, indicating that the genetic background outside the H-2 complex also influences survival. The congenic F1 hybrid (C57BL/10 X B10.S) F1 exhibited intermediate survival levels when compared with the parental strains, indicating that H-2S survival is affected by gene dosage. The F1 hybrid strain [B10.S(7R) X B10.S(8R)]F1, which possesses the complete H-2S haplotype in the trans configuration, did not survive T. cruzi infection, suggesting that H-2S-mediated survival does not operate by trans complementation.     

Experimental Autoimmune Thyroiditis (EAT) Induced by the Thyroglobulin Peptide (2596–2608): Influence of H-2 and Non H-2 Genes

We have previously identified five thyroglobulin (Tg) peptides with A^k-binding motifs that induce experimental autoimmune thyroiditis (EAT) in CBA/J (H-2^k) mice. In this study, we have examined whether H-2 or non H-2 genes can influence the immunopathogenicity of peptide p2596 (a.a. 2596–2608), which earlier elicited considerable pathology in CBA/J hosts. The p2596 peptide induced mild EAT—(infiltration index range=1–2)— in H-2-compatible AKR/J, B10.BR, and C3H/HeJ mice. Moreover, p2596-primed LNC from these mice exhibited peptide-specific proliferative responses and secreted significant amounts of IL-2 and IFN-γ in recall in vitro assays. Priming and boosting of these strains with p2596 resulted in the generation of specific IgG responses five weeks after the initial challenge. In contrast, s.c. challenge of H-2-incompatible strains such as DBA/1J (H-2^q), SJL (H-2^s), DBA/2J (H-2^d) and C57BL/6 (H-2^b) with the same peptide dose did not elicit EAT pathology and peptide-specific B- or T-cell responses. These data demonstrate the thyroiditogenic potential of p2596 in H-2^k strains of diverse non-H-2 backgrounds but not in mice carrying H-2^{b, d, q?or?s} haplotypes.     

IgG subclass responses to Theiler's murine encephalomyelitis virus infection and immunization suggest a dominant role for Th1 cells in susceptible mouse strains.

Inbred mouse strains differ in susceptibility to Theiler's murine encephalomyelitis virus (TMEV)-induced demyelinating disease. A strong correlation between disease susceptibility and delayed-type hypersensitivity (DTH) has been previously demonstrated, but no strong correlation between disease susceptibility and total anti-TMEV ELISA titres was shown. Since both DTH and IgG2a antibody production are regulated by CD4+ Th1 cells, we investigated three strains of mice to determine whether antivirus IgG2a antibody levels, like DTH in previous studies, correlated with disease susceptibility. Susceptible SJL/J, intermediately susceptible C3H/HeJ, and resistant C57BL/6 mice were infected intracerebrally (i.c.) with the BeAn strain of TMEV and monitored for clinical signs of demyelination and for levels of TMEV-specific antibody of different IgG subclasses using a particle concentration fluorescence immunoassay (PCFIA). Resistant C57BL/6 mice were found to have significantly lower concentrations of total anti-TMEV antibody than susceptible SJL/J mice and intermediately susceptible C3H/HeJ mice show variable antibody responses. A predominance of anti-TMEV IgG2a (Th1 regulated) antibody was seen in susceptible and intermediately susceptible mice, whereas resistant mice displayed a predominant anti-TMEV IgG1 (Th2 regulated) response accompanied by a marked deficiency of IgG2a. In contrast, immunization of C57BL/6 mice with UV-inactivated TMEV in adjuvant revealed that this strain was not defective either in its ability to generate high levels of anti-TMEV antibody or in its ability to produce IgG2a antibody. These results suggest that the antivirus IgG subclass profile is dependent upon the immunization route, virus viability and/or the use of adjuvant and that the levels of antivirus subclasses may be predictive of disease susceptibility.     

Defective immunoglobulin M responses to vaccination or infection with Schistosoma mansoni in xid mice.

Mice vaccinated with irradiated Schistosoma mansoni cercariae develop a persistent immunoglobulin M (IgM) antischistosomulum antibody response. To investigate the possible role of antilarval IgM antibodies in the effector mechanism of vaccine-induced immunity, CBA/N mice, which have an X-linked genetic defect resulting in impaired IgM antibody responses to certain antigens, were analyzed for their resistance to a challenge infection. When either infected with unattenuated parasites or vaccinated with irradiated cercariae, mice of this inbred strain failed to produce detectable IgM antibodies to schistosomulum surface membrane and soluble worm antigens. To analyze the effect of this IgM deficiency on immunity, F1 hybrids were constructed between CBA/N females and nondefective C57BL/6J males. As expected, vaccinated (CBA/N X C57BL/6J)F1 females, as well as (CBA/J X C57BL/6J)F1 males and females, produced normal IgM antibodies to both surface antigens and worm antigen extracts. However, such antibodies were not produced by (CBA/N X C57BL/6J)F1 males (hemizygous for xid). Nevertheless, (CBA/N + C57BL/6J)F1 males displayed the same high levels of immunity to challenge infection as (CBA/N X C57BL/6J)F1 females and (CBA/J X C57BL/6J)F1 males and females. These results indicate that vaccine-induced immunity is not dependent on an IgM response to schistosome antigens.     

TNF accelerates the onset but does not alter the incidence and severity of myelin basic protein-induced experimental autoimmune encephalomyelitis

Experimental autoimmune encephalomyelitis (EAE) induction in TNF gene-targeted mice has resulted in conflicting reports in part due to the strong association of TNF with the MHC locus. To define the participation of TNF in EAE development, we back-crossed TNF-deficient mice (H-2b) into the SJL/J strain and directly compared them to H-2b congenic SJL or inbred SJL/J mice. Induction of EAE with myelin basic protein (MBP) revealed that H-2b congenic SJL mice are fully susceptible, indicating that the H-2b haplotype does not affect disease susceptibility. Using H-2b congenic SJL mice we show here that TNF deficiency modifies the normal course of EAE by considerably delaying the onset for approximately 5 days, suggesting that TNF is required for the normal initiation of MBP-induced EAE. However, TNF-deficient mice eventually developed severe EAE with perivascular inflammation and primary demyelination similar to wild-type controls, indicating that TNF is not essential during these processes. Taken together, these results indicate that although TNF is not required for the progression of MBP-induced EAE, it contributes positively by advancing the onset of disease.     

Cellular requirements for anti-DNA production induced in mice by immunization with bacterial DNA

To further define DNA immunization as a model for anti-DNA production, we investigated the cellular requirements for this response in mice immunized with single-stranded DNA from E. coli. The anti-DNA responses of genetically immune-deficient mice and congenic controls were measured by ELISA after immunization with E. coli DNA as complexes with methylated bovine serum albumin in complete Freund's adjuvant. T cell-deficient BALB/c-nu/nu mice failed to produce IgG anti-DNA by this protocol despite high backgrounds of IgM anti-DNA. In contrast, CBA/N mice expressing the xid defect displayed IgG anti-DNA responses comparable to those of CBA/J mice despite a reduced IgM response; the specificity of CBA/N and CBA/J anti-DNA antibodies was similar as determined by binding to synthetic DNA and RNA antigens. These results suggest that the anti-DNA response stimulated by DNA immunization is dependent on T cells but not the B cell population affected by xid. The intact IgG response of immunized xid mice differs from that of lupus mice bearing xid where this gene defect leads to significant reduction of spontaneous anti-DNA production.     

H-2 linked genetic control of immune responsiveness to hepatitis B surface antigen (HBsAg) in mice

Recent data suggest that genes involved in the control of (1) immune responses of humans to HBsAg and (2) the susceptibility to the development of chronic hepatitis B are linked to the major HLA histocompatibility complex. Studies on the genetic regulation of anti-HBs responses and on the possible abrogation of nonresponsiveness to HBsAg in humans are difficult. In an attempt to develop a relevant animal model system, the anti-HBs response of inbred and congenic strains of mice was investigated. A great variation in anti-HBs responses among individual mice belonging to the same strains was observed. Nevertheless, it was possible to rank the inbred mouse strains studied according to their decreasing anti-HBs responses as follows: BALB/c[d] ∽ SWR/J[q] > C57BL/6J[b] ∽ DBA/2J[a] > AKR/J[k] > A/J[a] > CBA/CaJ[k] > SJL/J[s]. (Letters in brackets indicate H-2 haplotype). Only a small proportion of SJL mice had an anti-HBs response. Therefore, this strain may serve as a model for human nonresponders. Studies with the congenic strains B10.D2[d] and B10.S[s] indicated that genes conferring responsiveness to HBsAg are linked to the H-2 histocompatibility complex. However, genes not linked to H-2 also probably play a role in regulating anti-Hbs responses.     

Genetic control of Salmonella typhimurium-induced depression of delayed-type hypersensitivity to sheep erythrocytes in mice.

Infection of mice with a temperature-sensitive mutant of Salmonella typhimurium C5TS allowed the survival of genetically susceptible mice. The ability to mount a delayed-type hypersensitivity (DTH) response to sheep erythrocytes during infection with C5TS was studied in various inbred mouse strains, recombinant inbred strains derived from C57BL/6 (susceptible) and A/J (resistant) mice, and C3H congenic mice. Suppression of the DTH response to sheep erythrocytes was found in mice that carried the Itys allele, the H-2b haplotype, or both. These genes are known to increase susceptibility to S. typhimurium infection. In contrast, no DTH response suppression was observed in mouse strains that carried other genes that increased susceptibility to S. typhimurium, e.g., DBA/2 and C3H/HeJ. Apart from a transient suppression in A/J mice, the DTH responses of resistant mice (A/J and CBA) were normal or increased. The DTH response to sheep erythrocytes could be restored in immunodepressed mice by increasing the immunizing dose, suggesting the possible role of activated macrophages in depression of the DTH response.     

Maturation of the filaria Litomosoides sigmodontis in BALB/c mice; comparative susceptibility of nine other inbred strains.

When inoculated subcutaneously, the infective larvae of L. sigmodontis undergo complete development and produce a patent microfilaraemia in mice of the BALB background (BALB/c, BALB/K and BALB/B, with respectively the H-2d, H-2k et H-2b haplotypes). The most susceptible strain is BALB/c with all mice harbouring adult filariae and 47% of mice presenting with a patent microfilaraemia. Mice with the B10 background (B10, B10Br and B10D2, with respectively the H-2b, H-2k et H-2d haplotypes) are almost completely resistant to infection. Adult filariae were recovered from all mice of the CBA/Ca, CBA/HN, C3H/HeN, DBA/2N strains. However, the site and structural development of the parasite varied in each strain. Absence of microfilaraemia is associated with absent or abnormal spicules, reduced number of female filariae and small size of female filariae. These results show that the Major Histocompatibility Complex only modulates the developmental pattern of filariae within the limits imposed by background genes. Male CBA/HN and C3H/HeN were more susceptible to infection than female mice. Inverse phenomenon was observed with strains BALB/c; and, no host sex effect was seen in DBA/D2N.     

Genetic control of resistance to Mycoplasma pulmonis infection in mice.

The differences in susceptibility of various inbred strains of mice to a highly pathogenic strain of Mycoplasma pulmonis CT (T2) has been known for some time. We assessed the genetic control of resistance to T2 infection. Tracheolung lavage samples and lungs of mice were assessed for T2 organisms after intratracheal injection of T2. We found that H-2b (C57BL/6 (B6) and H-2k B10.BR mice were resistant, whereas H-2b A.By, H-2k C3H/Bi, H-2k C3H/HeJ (C3H), and H-2b BALB.B mice were susceptible. We also typed individual B6C3F2 mice for H-2 and for resistance to T2 and observed that resistance to T2 infections is controlled by a single dominant gene not linked to H-2. Histologic examination revealed severe lung lesions typical of M. pulmonis infections in susceptible C3H mice, in contrast to minimal lung lesions in resistant B6 mice. No significant titers of local or systemic antimycoplasma antibodies were detected in either resistant or susceptible mice at 5 days postinfection. Macrophages taken from uninfected B6 or C3H mice failed to inhibit growth of T2 in vitro. However, macrophages from B6 mice did inhibit growth of T2 much better than C3H macrophages when harvested on day 5 of infection. Thus, there is an association between activation of macrophage bactericidal function and genetic resistance to growth of T2 organisms.