Experimental allergic encephalomyelitis in connexin 43-heterozygous mice

Alterations in the expression of gap junction proteins (connexins) have previously been observed in experimental allergic encephalomyelitis (EAE). Demyelinating lesions have significantly decreased Cx43, while recovering lesions have greatly increased Cx43 and increased glial fibrillary acidic protein-expressing astrocytes. This suggests an important role for gap-junctional intercellular communication in astrocytes in the recovery from CNS inflammation. To study the effects of decreased Cx43 expression during acute disease (21 days post-immunization) and in recovering spinal cord tissue (55 days post-immunization) we induced EAE in Cx43 heterozygous and wild-type mice. Mice showed signs of disease by day 10, and signs of recovery by day 25. There were no clinical or pathological differences between heterozygous and wild-type mice in the acute disease stage, except that wild-type male mice had fewer clinical signs of disease. Male mice that were heterozygous for Cx43, and therefore had decreased expression of Cx43, had increased EAE disease severity. All demyelinating lesions had reduced numbers of reactive astrocytes and a significant decrease in Cx43 expression. In the 55-day study, all heterozygous and wild-type mice were clinically improved, showed decreased pathological signs, and showed increased laminin expression, indicative of CNS recovery. Furthermore, all heterozygous mice showed a striking increase in Cx43 expression during recovery, suggesting that the regulatory factors affecting Cx43 expression are still present in mice that have only one wild-type Cx43 allele.     

Experimental allergic encephalomyelitis is inhibited in transgenic mice expressing human C-reactive protein

We show here using a transgenic model that human C-reactive protein (CRP) protects against experimental allergic encephalomyelitis (EAE) in C57BL/6 mice. In transgenic compared with wild-type females, the duration of the human CRP acute phase response that accompanies the inductive phase of active EAE correlates with a delay in disease onset. In transgenic males, which have higher human CRP expression than females do, EAE is delayed, and its severity is reduced relative to same-sex controls. Furthermore, in male transgenics, there is little or no infiltration of the spinal cord by CD3(+) T cells and CD11b(+) monocytes and macrophages, and EAE is sometimes prevented altogether. CRP transgenics also resist EAE induced passively by transfer of encephalitogenic T cells from wild-type donors. Human CRP has three effects on cultured encephalitogenic cells that could contribute to the protective effect observed in vivo: 1) CRP inhibits encephalitogenic peptide-induced proliferation of T cells; 2) CRP inhibits production of inflammatory cytokines (TNF-alpha, IFN-gamma) and chemokines (macrophage-inflammatory protein-1alpha, RANTES, monocyte chemoattractant protein-1); and 3) CRP increases IL-10 production. All three of these actions are realized in vitro only in the presence of high concentrations of human CRP. The combined data suggest that during the acute phase of inflammation accompanying EAE, the high level of circulating human CRP that is achieved in CRP-transgenic mice inhibits the damaging action of inflammatory cells and/or T cells that otherwise support onset and development of EAE.     

Myelin proteolipid protein-induced experimental allergic encephalomyelitis. Variations of disease expression in different strains of mice

Strains of mice with diverse genetic backgrounds were tested for susceptibility to experimental allergic encephalomyelitis (EAE) induced by myelin proteolipid protein. EAE was elicited in all strains of mice tested, but the clinical and histologic features varied. SJL (H-2s) mice had a high incidence of both clinical and histologic disease characterized by early onset of clinical signs. Inguinal lymph node T cells from diseased animals responded specifically [( 3H]thymidine incorporation) to proteolipid protein and not to myelin basic protein. In contrast, BALB/c (H-2d), DBA/1 (H-2q), C57BL/6 (H-2b), AKR (H-2k), CBA (H-2k), C3H (H-2k), B10.BR (H-2k), and C57BR (H-2k) mice showed a later onset of clinical signs and typically a lower disease incidence. However, the most marked variations in disease incidence occurred among BALB/c (H-2d) substrains in which the incidence of EAE ranged from eight of nine (BALB/cPt) to complete resistance (BALB/cWt and BALB/cORNL). Because these BALB/c substrains were initially derived from the same inbred genetic source and are serologically identical at H-2, these results suggest that expression of proteolipid protein-induced EAE in the mouse involves additional loci outside the MHC.     

Acute experimental allergic encephalomyelitis in radiation bone marrow chimeras between high and low susceptible strains of mice

Acute experimental allergic encephalomyelitis (EAE) is an autoimmune disease involving the central nervous system (CNS) that can be elicited in susceptible strains of mice by the subcutaneous inoculation of mouse spinal cord homogenate (MSCH) in conjunction with complete Freund's adjuvant. In order to localize the physiological compartment conveying susceptibility to mice for EAE induction, hematopoietic radiation chimeras were prepared between the highly responsive SJL and low responder B10.S strains. Upon challenge with SJL MSCH preparations, high incidence of clinical disease was exhibited by B10.S SJL chimeras but not by SJL B10.S mice, suggesting that non-bone-marrow-derived factors were influencing development of disease. The incidence of histological lesions in the CNS was high for virtually all experimental and control groups except normal B10.S and B10.S B10.S reconstituted mice. In contrast, challenge with B10.S MSCH induced a high clinical incidence of EAE in both B10.S SJL and SJL B10.S chimeras, indicating a possible interstrain difference in the immunogenicity of relevant CNS antigens.Abbreviations used in this paper APC antigen-presenting cell - C complement - CFA complete Freund's adjuvant - CNS central nervous system - EAE experimental allergic encephalomyelitis - MBP myelin basic protein - MHC major histocompatibility complex - MSCH mouse spinal cord homogenate - PBS phosphate-buffered saline     

Experimental allergic encephalomyelitis in guinea pigs caused by meningococci

The sensitization of guinea-pigs with the mixture of meningococci and heterologous-cerebral tissue commonly induces the development of the typical clinical and pathomorphological picture of allergic encephalomyelitis. Unlike Mycobacterium tuberculosis and other acid-resistant bacterial and much like Bordetella pertussis, meningococci are capable of inducing allergic encephalomyelitis when introduced in mixture with oil without cerebral tissue. The vaccinal strain induces allergic encephalomyelitis with a more moderate course of the disease.     

Experimental allergic orchitis in mice

Susceptibility to the induction of murine autoimmune orchitis was found to be associated with the locus controlling Bordetella pertussis-induced sensitivity to the vasoactive amine, histamine. Only those inbred and H-2 congenic strains of mice possessing both the H-2 ^d haplotype and the locus for susceptibility to B. pertussis-induced sensitivity to histamine developed autoimmune orchitis. In addition, segregation analysis of backcross generation mice also demonstrated a high degree of correlation between susceptibility both to disease and to histamine sensitization, which was indicative of additional multigene control. Pertussigen-histamine sensitization factor (P-HSF) was only effective in eliciting disease when it was administered on the same day, or within a period up to 6 days following sensitization with mouse testicular homogenate-emulsified in complete Freund's adjuvant. P-HSF induced sensitivity to histamine was not found to be associated with an increase in the vascular permeability of target tissue. Thus, B. pertussis-induced sensitivity to histamine appears to play a more crucial role during the sensitization phase of autoimmune orchitis induction, rather than at the inflammatory or effector phase of the disease.     

Specific immune regulation of chronic-relapsing experimental allergic encephalomyelitis in mice

These studies were designed to examine immunologic means of regulating the clinical course of murine chronic-relapsing experimental allergic encephalomyelitis (R-EAE). We asked whether induction of specific immune tolerance to the major CNS myelin proteins, myelin basic protein (MBP) and proteolipid protein (PLP), could inhibit the development of R-EAE. Neuroantigen-specific tolerance was induced in SJL/J mice in a dose-dependent manner by the i.v. injection of mouse spinal cord homogenate-coupled syngeneic splenocytes (MSCH-SP) on day -7 relative to immunization on days 0 and +7. Sham-tolerized controls developed significant MBP- and PLP-specific DTH responses before the onset of clinical R-EAE. In contrast, MSCH-SP tolerized mice exhibited a dramatically reduced incidence of clinical and histologic signs of disease which correlated with the failure to develop MBP- and PLP-specific DTH responses. In 10 separate experiments, 118/149 (79%) of control mice, but only 22/137 (16%) of tolerized mice developed clinical R-EAE. Tolerance took time to develop and lasted at least 4 wk as mice injected with Ag-coupled splenocytes on day -1 relative to immunization remained susceptible to R-EAE, whereas mice injected on days -7, -14, or -28 were resistant. Tolerance induction required neuroantigens as injection of splenocytes coupled with a syngeneic mouse kidney homogenate failed to significantly alter the incidence of R-EAE or the development of neuroantigen-specific DTH responses. Thus, induction of R-EAE can be specifically and significantly regulated after the i.v. injection of splenocytes coupled with a crude, heterogeneous mixture of neuroantigens (i.e. MSCH).     

Genetic control of susceptibility to experimental allergic encephalomyelitis in mice

The genetic control of susceptibility to experimental allergic encephalomyelitis (EAE) was studied in mice. The results indicate that sensitivity to disease is not inherited in a simple Mendelian dominant way. Susceptibility to EAE is governed by genes located outside of the major histocompatibility complex and not byH-2-linkedIr genes. No correlation was observed between susceptibility to disease and the cellular immune response toward the small encephalitogenic protein.     

Experimental allergic orchitis in mice

Inbred strains of mice were studied for their susceptibility to the induction of experimental allergic orchitis after sensitization with mouse testicular homogenate in complete Freund's adjuvant accompanied by injections of extract from Bordetella pertussis. Susceptibility to autoimmune orchitis was found to be linked to the major histocompatibility complex in BALB/c and C57BL/10 mice and mapped to genes encoded within the H-2D ^dregion. In five of six groups of bidirectional (susceptible × resistant) F₁ hybrids, H-2D ^d-linked susceptibility was inherited as a dominant autosomal trait. However, in (BALB/cByJ × DBA/2J)F₁ and (DBA/2J × BALB/cByJ)F₁ hybrids, dominant autosomal resistance to the induction of autoimmune orchitis was observed. Backcross analysis between the resistant F₁ hybrid and the susceptible BALB/cByJ parent suggests that a single independently segregating DBA/2J locus is capable of negating H-2D ^d-linked susceptibility, and controls resistance to the induction of autoimmune orchitis.Abbreviations used in this paper BP extract Bordetella pertussis extract - CFA complete Freund's adjuvant - EAO experimental allergic orchitis - Ir immune response - MHC major histocompatibility complex - MLH mouse liver homogenate - MTH mouse testis homogenate - PI pathology index     

The immunologic response in mice unresponsive to experimental allergic encephalomyelitis

The suppressor cells that are involved in antigen-induced protection against EAE in mice were investigated with respect to their effect on the immune response. The cellular immune response to the basic encephalitogenic protein (BE) and to PPD were studied in mice with either actively induced or adoptively transferred unresponsiveness to EAE. The results demonstrate that the DTH response to BE, as assayed in the radiometric ear skin test, was suppressed in mice protected against EAE. Moreover, the passive transfer of DTH response to BE by effector lymphocytes was also inhibited by the preinjection of suppressor cells. On the other hand, the suppressor cells did not affect the response to PPD in all these experiments. The results indicate that suppressor cells that mediate unresponsiveness to EAE regulate also the cellular immune response to BE in a specific manner. These suppressor cells are probably active both at the induction and the effector phase of the immune response.     

Experimental allergic encephalomyelitis and cellular immunity in the Lewis rat

The encephalitogenic difference between purified guinea pig and bovine myelin proteins in the Lewis rat is reflected by the two molecules' lack of crossreactivity in the migration inhibition test. Peritoneal exudate cells from rats injected with guinea pig or bovine derived myelin basic protein in Freund's complete adjuvant demonstrate substantial migration inhibition to the sensitizing antigen but little inhibition when cultured in the presence of the other basic protein. The cellular reactivity to guinea pig basic protein is present throughout the induction phase of Experimental Allergic Encephalomyelitis and persists after the recovery of the rats from the paralytic state. Substantial cellular reactivity is also demonstrated to bovine basic protein even though this molecule shows minimal encephalitogenic activity in the Lewis rat. Minimal lymphocyte transformation could be demonstrated to either of the basic proteins, although the immune cells react strongly to the plant mitogen phytohemagglutinin and to a Mycobacterium tuberculosis antigen.