Antigen presentation to T cells by MHC molecules is essential for adaptive immune responses. To determine the exact position of a gene affecting expression of MHC molecules, we finely mapped a previously defined rat quantitative trait locus regulating MHC class II on microglia in an advanced intercross line. We identified a small interval including the gene MHC class II transactivator (Mhc2ta) and, using a map over six inbred strains combined with gene sequencing and expression analysis, two conserved Mhc2ta haplotypes segregating with MHC class II levels. In humans, a -168A --> G polymorphism in the type III promoter of the MHC class II transactivator (MHC2TA) was associated with increased susceptibility to rheumatoid arthritis, multiple sclerosis and myocardial infarction, as well as lower expression of MHC2TA after stimulation of leukocytes with interferon-gamma. We conclude that polymorphisms in Mhc2ta and MHC2TA result in differential MHC molecule expression and are associated with susceptibility to common complex diseases with inflammatory components.

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In experimental autoimmune encephalomyelitis (EAE), CD4(+) self-reactive T cells target myelin components of the CNS. However, the consequences of an autoaggressive T cell response against myelin for neurons are currently unknown. We herein demonstrate that EAE induced by active immunization with an encephalitogenic myelin basic protein peptide dramatically reduces the loss of spinal motoneurons after ventral root avulsion in rats. Both brain-derived neurotophic factor (BDNF)- and neurotrophin-3 (NT-3)-like immunoreactivities were detected in mainly T and natural killer (NK) cells in the spinal cord. In addition, very high levels of BDNF, NT-3, and glial cell line-derived neurotrophic factor mRNAs were present in T and NK cell populations infiltrating the CNS. Interestingly, bystander recruited NK and T cells displayed similar or higher neurotrophic factor levels compared with the EAE disease-driving encephalitogenic T cell population. High levels of tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) mRNAs were also detected, and both these cytokines can be harmful to several types of CNS cells, including neurons. However, treatment of embryonic motoneuron cultures with TNF-alpha or IFN-gamma only had a deleterious effect in cultures deprived of neurotrophic factors. These results suggest that the potentially neurodamaging consequences of severe CNS inflammation are curbed by the production of several potent neurotrophic factors in leukocytes.

Neurodegeneration and inflammation are fundamental aspects of many neurological diseases. A genome-wide scan of the response to ventral root avulsion (VRA) in a rat F2 cross discloses specific gene regions that regulate these processes. Two gene loci displayed linkage to neurodegeneration and T cell infiltration, respectively, and a single locus displayed extreme linkage to VRA-induced major histocompatibility complex class II expression on microglia. The demonstration that polymorphic genes in different loci control neurodegeneration and CNS inflammation has implications for various experimental rodent nervous system paradigms and potentially for genetically regulated susceptibility to a variety of human CNS diseases.

Recent discoveries suggest that the resident cells of the central nervous system (CNS) the nerve cells and glia, play a more immunologically active role than was previously assumed. Neuroglial communication is of central interest in virtually all types of pathological conditions that affect the brain and several features of the activation that results from nerve cell damage resemble the type of innate immune reactions that occur in other parts of the body In particular, the characteristics of the activation of these CNS cells will affect both the interaction with cells of the immune system as well as processes related to neurodegeneration and regeneration. We here review data regarding 3 different aspects of local inflammatory activation in the rat nervous system: (i) the genetic heterogeneity of glial activation across inbred strains after nerve injury, (ii) expression of MHC class I genes in the CNS and (iii) neuroprotective effects of CNS antigen autoreactive immune reactions. Apart from neuroimmune diseases such as experimental autoimmune encephalomyelitis/multiple sclerosis, these features are also of relevance for a wider range of neurological diseases which present pathological signs of inflammation, such as Alzheimer's dementia, cerebrovascular diseases and CNS trauma.

Ventral root avulsion in the rat leads to a retrograde response, with activation of glia and up-regulation of immunologic cell surface molecules such as major histocompatibility complex (MHC) antigens, and the subsequent degeneration of a large proportion of the lesioned motoneurons. Herein, we examined several inbred congenic rat strains previously known to react differently to experimentally induced autoimmune diseases and demonstrate a substantial genetic diversity in the regulation of glial activation and neuron death in this injury model. The panel of examined inbred rat strains included DA(RT1AV1), PVG.1AV1, LEW.1AV1, LEW.1N, BN(RT1N) and E3(RT1U), and the following parameters were determined: (1) MHC class II expression on glia; (2) expression of glial fibrillary acidic protein, C3 complement, and microglial response factor-1 mRNAs in glia; (3) levels of the tumor necrosis factor-alpha and interleukin-1beta cytokine mRNAs; (4) degree of motoneuron loss. The findings of considerable strain-dependent differences in all parameters studied demonstrate important polymorphisms in the genetic regulation of these events. Furthermore, some of the studied features segregated from each other, suggesting independent regulatory mechanisms. Genes outside of the MHC complex are mainly implicated as being of importance for the phenotypic differences, as significant differences were recorded between the MHC congenic strains differing in the non-MHC genes but not vice versa. These results contribute new important insights into the genetic regulation of glial reactivity and neuron death after mechanical nerve injuries. In addition, the finding of conspicuous strain-dependent differences makes it necessary to consider the genetic background when designing and interpreting animal experiments involving noxious insults to the central nervous system resulting in glial activation and nerve cell loss.

Major histocompatibility complex (MHC) class I genes consist of classical (Ia) and nonclassical (Ib) types. Recently, a set of structurally similar MHC class Ib genes in the rat, denoted RT1-U, was described. We here demonstrate expression of RT1-U mRNA using highly stringent oligonucleotide in situ hybridization in several different neuronal populations, including different motor nuclei and the substantia nigra in the rat MHC (c) and (n) haplotypes under normal conditions. The expression pattern for beta2-microglobulin mRNA was almost identical. In contrast, neuronal expression of classical MHC class I (RT1-A) was low. Interestingly, after mechanical nerve injury, glial cells predominantely upregulated expression of RT1-A, whereas neuronal expression of RT1-U remained unchanged. Neuronal expression of nonclassical MHC class I may thus be important for immune surveillance in the nervous system.

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