Vacuolar myositis with expression of both MHC class I and class II antigens on skeletal muscle fibers.

We describe here a 10-year-old patient with high levels of serum IgE and inflammatory myopathy whose muscle fibers exhibit excessive autophagy. Previous studies have demonstrated surface expression of class I MHC antigens on muscle fibers from patients with inflammatory myopathy. The muscle fibers of this patients showed marked expression of both class I and class II MHC antigens. The reaction products were demonstrated not only on sarcolemma but also in and around some vacuoles. Both CD4-positive and CD8-positive T-lymphocytes were noted in inflammatory exudates surrounding these fibers but B-lymphocytes were rare. We hypothesize that myocyte expression of both class I and class II antigens may play a role in the pathogenesis of this new type of inflammatory myopathy.     

Expression of major histocompatibility complex class I and class II antigens in canine masticatory muscle myositis

Studies in human immune-mediated inflammatory myopathies have documented expression of major histocompatibility complex class I (MHC class I) and class II (MHC class II) antigens on muscle fiber membranes in the presence or absence of cellular infiltration. Here we evaluate the presence and distribution of these antigens in canine masticatory muscle myositis, an immune-mediated inflammatory myopathy. Twelve samples of temporalis and masseter muscles from dogs with a clinical diagnosis of canine masticatory muscle myositis were examined by immunohistochemistry and double-immunofluorescence confocal microscopy. MHC class I and class II antigens were expressed in muscle fibers independent of inflammatory cell infiltration. Furthermore MHC class I and class II antigens were expressed on the sarcolemma and co-localized with dystrophin. Our results suggest that MHC class I and class II expression in canine masticatory muscle myositis may play a role in the initiation and maintenance of the pathological condition, rather than just a consequence of a preceding local inflammation.     

Interleukin-4 down-regulates MHC class II antigens on cultured rat astrocytes

Mammalian cerebral astrocytes can be brought to express major histocompatibility complex (MHC) class II molecules upon appropriate stimulation. It is well established that this expression is subject to modulation by several neurotransmitters and cytokines. We show that the low, basal expression of MHC class II antigens on cultured rat astrocytes is concentration-dependently down-regulated by low concentrations of interleukin-4 (IL-4), reaching maximal inhibition at 10 U/ml. The higher, γ-IFN-induced, expression of class II molecules is also decreased by increasing concentrations of IL-4, significant effects being already observed at 5 U/ml. Since the cAMP as well as the nitric oxide dependent cGMP pathway have previously been shown to mediate an inhibition on astroglial MHC class II expression, we measured the intra-cellular content of cyclic nucleotides after stimulation with IL-4. No rise in cAMP or cGMP is detected. Similarly, IL-4 does not affect the induced synthesis of nitric oxide radicals. Since MHC class II expression is a critical step in many regulatory processes of the cellular immune reaction, IL-4, via its activity on astroglial cells, emerges as an important modulator of immunological activities in the central nervous system. © 1996 Wiley-Liss, Inc.     

The identity of cells expressing MHC class II antigens in normal and pathological human brain

Major histocompatibility complex class II antigen (Ag) expression in human brain was investigated in autopsied human brain tissues, using anti-human class II monoclonal antibodies. In normal brains, class II Ag was usually absent or was low in positivity. When it was found immunohistochemically, it appeared more frequently in the meninges (meningeal macrophages) and the neurohypophysis (pituicytes) than in the cerebral cortex (microglia and perivascular cells). The identity of the latter cell types was confirmed by immunoelectron microscopy. Class II-positive microglial cells were usually present in the cerebral white matter, but in senile brains showing numerous senile plaques, their numbers were increased in the grey matter. In diseased brains, numerous reactive microglia and macrophages containing class II Ag were observed in the affected lesions of neural tissue destruction, neuronal degeneration, and inflammation. Astrocytes, which were identified with an antibody to glial fibrillary acidic protein, did not contain class II Ag, although a small number of reactive astrocytes showed an equivocal class II staining. Staining for class II Ag on cerebral endothelial cells was mostly negative; however, class II Ag was microscopically identified in a case of secondary CNS T-cell lymphoma.     

Tumor necrosis factor induces expression of MHC class I antigens on mouse astrocytes

The effect of tumor necrosis factor (TNF) on expression of major histocompatibility complex (MHC) antigens was examined in mouse glial cells in vitro. TNF induced MHC class I, but not class II, antigen expression on the surface of astrocytes but not on oligodendrocytes. Glial cells do not normally express detectable amounts of MHC antigens. Thus TNF may play a role in the immunopathogenesis of neurologic diseases that involve MHC class I-restricted reactions.     

Mouse Schwann cells activate MHC class I and II restricted T-cell responses,but require external peptide processing for MHC class II presentation

Schwann cells are the myelinating glia cells of the peripheral nervous system (PNS). In inflammatory neuropathies like the Guillain-Barré syndrome (GBS) Schwann cells become target of an autoimmune response, but may also modulate local inflammation. Here, we tested the functional relevance of Schwann cell derived MHC expression in an in vitro coculture system. Mouse Schwann cells activated proliferation of ovalbumin specific CD8+ T cells when ovalbumin protein or MHC class I restricted ovalbumin peptide (Ova_257–264 SIINFEKL) was added and after transfection with an ovalbumin coding vector. Schwann cells activated proliferation of ovalbumin specific CD4+ T cells in the presence of MHC class II restricted ovalbumin peptide (Ova_323–339 ISQAVHAAHAEINEAGR). CD4+ T-cell proliferation was not activated by ovalbumin protein or transfection with an ovalbumin coding vector. This indicates that Schwann cells express functionally active MHC class I and II molecules. In this study, however, Schwann cells lacked the ability to process exogenous antigen or cross-present endogenous antigen into the MHC class II presentation pathway. Thus, antigen presentation may be a pathological function of Schwann cells exacerbating nerve damage in inflammatory neuropathies.     

Vasoactive intestinal polypeptide inhibits the expression of the MHC class II antigens on astrocytes

The brain has been traditionally viewed as an immunologically privileged site. However, recent findings suggest that the brain is in fact equipped with its own immune circuitry. Astrocytes and microglia have been considered the most likely candidates to assume the role of intracerebral antigen presenting cells (APC). Using the techniques of immunofluorescence cytochemistry and flow cytometric analysis, we observed that vasoactive intestinal polypeptide (VIP) can significantly inhibit gamma-interferon (IFN-gamma)-induced Ia expression on astrocytes derived from newborn Lewis rats. Further, we analyzed a number of neuropeptides and transmitters for their ability to exert a similar inhibitory modulation on IFN-gamma induced Ia expression or for the ability to induce or augment Ia expression on rat astrocytes. Our results showed that only norepinephrine (NE), a major brain neurotransmitter, and VIP, a ubiquitous brain peptide, have the ability to inhibit Ia expression on Lewis rat astrocyte cultures. Alternately, we report that cholecystokinin (CCK), a brain/gut peptide, has the ability to induce Ia on about 5-10% of the cells analyzed. These findings suggest that endogenous brain substances have the ability to modulate intracerebral immune responses by regulating the expression of Ia on astrocytes.     

Contribution of the MHC class II antigens to the etiology of infantile spasm in Mexican Mestizos

PURPOSE: Infantile spasms (ISs) are age-dependant epileptic seizures, which may be flexor, extensor, lightning or nods, or mixed. The aim of this study was the analysis of genetic factors within the human leukocyte antigen (HLA) complex associated with ISs. METHODS: Sixty-five patients diagnosed according to the established international criteria were compared with 229 healthy individuals; all of them were Mexican Mestizos. Five families were also analyzed (seven affected and five healthy sibs); HLA class I and class II antigens were typed using the standard microlymphocytotoxicity methods. RESULTS: The findings showed female gender preference (2:1). Two thirds were symptomatic, and prevalent seizures were of mixed type (67%). A strong association with HLA-DR17 was detected in the IS group (pc < 0.01; OR = 3.6; EF = 0.20). DR17 was also found increased in the symptomatic patients (p = 0.009; OR = 3.16) and in those with other types of seizures (p = 0.001; OR = 2.0). Conversely, HLA-DQ6 was significantly decreased (pc < 0.002; PF = 0.37) in the total and in the symptomatic groups (p < 0.01). Haplotype linkage was not confirmed in the families; however, those with more than one affected sib shared at least one haplotype. CONCLUSIONS: These findings suggest the contribution of DR locus to the susceptibility and the participation of DQ region in the resistance to IS. Severity seems also to be influenced by HLA-DR17, and therefore class II typing may be a helpful tool for disease prognosis.     

Peripheral nerve injury causes transient expression of MHC class I antigens in rat motor neurons and skeletal muscles

After a peripheral nerve lesion (rat facial and sciatic) an induction of major histocompatibility complex (MHC) antigens class I was detected immunohistochemically in skeletal muscle fibers and motor neurons. This MHC expression was transient after a nerve crush, when regeneration occurred, but persisted after a nerve cut, when regeneration was prevented. Since the time course of MHC class I expression correlates to that of regeneration a role for this cell surface molecule in regeneration may be considered.     

Expression of lymphocyte, macrophage and class I and II major histocompatibility complex antigens in normal human dorsal root ganglia.

We analyzed the expression of lymphocyte, macrophage and class I and II (HLA-DR) major histocompatibility complex (MHC) antigens in normal dorsal root ganglia (DRG) from 19 patients without neurological disease by using an avidin-biotin immunoperoxidase technique. Satellite cells expressed class I and II MHC antigens. The intensity of HLA-DR staining varied among the DRG and was not related to age, history of cancer or infection, or number of T lymphocytes in the DRG. Monoclonal antibodies EBM11 and Leu-M3, that recognize cells of monocyte/macrophage lineage, stained a population of cells in all DRG. Positive cells had an elongated shape and were in the interstitial tissue between the satellite cells. These findings may be relevant to the understanding of the immune mechanisms involved in the neuronal damage of sensory neuropathies of presumably autoimmune origin such as those associated with small-cell lung cancer or Sj?gren's syndrome.     

Rat ependyma and microglia cells express class II MHC antigens after intravenous infusion of recombinant gamma interferon

Recombinant rat gamma-interferon was administered to Lewis rats by continuous intravenous infusion. After a 3-day administration period, at various dosages, a constant pattern of class II major histocompatibility complex (MHC) antigen induction was found in the brains and cerebella. Immunohistological double staining for class II antigens and glial fibrillary acidic protein showed that the majority of newly induced cells were microglia. The endothelium of large blood vessels and ependymal cells also expressed class II antigens. These findings demonstrate that systemically raised interferon levels can affect MHC antigen expression in the brain. Astrocytes are obviously not the primary cell type to acquire class II reactivity, and thus potential antigen-presenting capacity, in this situation.     

Induction of class I and class II transplantation antigens in rat brain during fatal and non-fatal measles virus infection

Measles virus induced a marked increase in the expression of MHC-coded class I and class II antigens as detected by immunostaining during both fatal and non-fatal brain infections in rats. The distribution of these molecules in the brain was much more widespread than the occurrence of viral antigen suggesting a soluble factor for their induction. In 14-day-old rats with a non-fatal infection there was a marked infiltration of T lymphocytes of 'cytotoxic/suppressor' phenotype in the brain parenchyma, whereas T 'helper' cell phenotypes mainly were located perivascularly. In brains from newborn rats with a fatal infection no or only few lymphocytes were detected.     

Associations with autoimmune disorders and HLA class I and II antigens in inclusion body myositis

Whether autoimmune mechanisms play a role in the pathogenesis of inclusion body myositis (IBM) is unknown. Human leukocyte antigen (HLA) analysis in 52 patients, including 17 with autoimmune disorders (AIDs), showed that patients were more likely to have antigens from the autoimmune-prone HLA-B8-DR3 ancestral haplotype than healthy control subjects, irrespective of the presence of AIDs. Patients lacked the apparently protective HLA-DR53 antigen. The results provide further support for an autoimmune basis in IBM.     

Differential induction of class I and II MHC antigen expression by degenerating myelinated and unmyelinated axons

Visual wulst responses to ipsi- and contralateral visual stimuli were investigated in young zebra finches (Taeniopygia guttata castanotis Gould) of different ages. Contralateral responses in 20, 40, 60 and 80 day old birds do not differ significantly from those in adults. In contrast, ipsilateral responses decrease substantially during development and become very weak and irregular in adult birds.     

Induction of MHC class I antigens on glial cells is dependent on persistent mouse hepatitis virus infection

H-2 class I antigens, but not class II antigens, were detected on the surface of glial cells persistently infected with mouse hepatitis virus strain A59 (MHV-A59) as late as 90 days post-infection. Uninfected glial cells remained negative for H-2 class I and class II surface antigens. We have previously shown that conditioned media from infected glial cell cultures (supernatants) contain a factor unrelated to infectious virus and capable of inducing H-2 class I antigens on uninfected glial cells. The synthesis of this factor appears to be dependent on production of infectious virus since the H-2 inducing activity could not be detected 3 days following the addition of neutralizing antibodies to the cultures. This suggests that H-2 inducing activity contains an unstable component, the synthesis of which is dependent on continual virus production. Persistent MHV infection and H-2 class I antigen expression may play a role in MHV-induced demyelination.     

Class II MHC antigens in normal human skeletal muscle.

Class II MHC antigen expression has been investigated in muscle tissue and cultured cells from normal human skeletal muscle by light and electron immunocytochemistry. In muscle tissue, these antigens were detected in satellite cells, interstitial cells, and blood vessels. In cultures, muscle cells were stained with a pan-reactive anti-HLA class II antibody and with isotypes specific for DP, DQ, and DR. The staining was present on mononucleated cells and persisted on myotubes; it was stronger for DR and DQ isotypes than for DP. At the subcellular level, staining was located not only at the cell surface, but also next to the endoplasmic reticulum and in the cytosol. Thus, myosatellite cells and aneurally cultured cells from human normal skeletal muscle express class II MHC antigens. Moreover, the myotube staining and the presence of gold particles inside the cells suggested synthesis of these antigens after myoblast fusion.     

Expression of MHC class I heavy chain and beta2-microglobulin in rat brainstem motoneurons and nigral dopaminergic neurons

We demonstrate here that motoneurons and nigral dopaminergic neurons in the brainstem of the adult rat, with the exception of motoneurons innervating ocular muscles, display high levels of both MHC class I heavy chain and beta2-microglobulin mRNAs. These neurons also display interferon-gamma receptor mRNA. We find it striking that these particular neurons are those which are vulnerable to neurodegeneration in diseases such as Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS).