myelin-oligodendrocyte-glycoprotein-(35-55) and Autoimmune-Diseases

The expression of nicotinic acetylcholine receptors by neurons, microglia, and astrocytes suggests possibly diverse mechanisms by which natural nicotinic cholinergic signaling and exposure to nicotine could modulate immune responses within the CNS. In this study, we show that nicotine exposure significantly delays and attenuates inflammatory and autoimmune responses to myelin Ags in the mouse experimental autoimmune encephalomyelitis model. In the periphery, nicotine exposure inhibits the proliferation of autoreactive T cells and alters the cytokine profile of helper T cells. In the CNS, nicotine exposure selectively reduces numbers of CD11c(+) dendritic and CD11b(+) infiltrating monocytes and resident microglial cells and down-regulates the expression of MHC class II, CD80, and CD86 molecules on these cells. The results underscore roles of nicotinic acetylcholine receptors and nicotinic cholinergic signaling in inflammatory and immune responses and suggest novel therapeutic options for the treatment of inflammatory and autoimmune disorders, including those that affect the CNS.

Topics: Amino Acid Sequence; Animals; Anti-Inflammatory Agents, Non-Steroidal; Autoimmune Diseases; Cell Differentiation; Cells, Cultured; Encephalomyelitis, Acute Disseminated; Female; Glycoproteins; Immunosuppressive Agents; Lymphocyte Activation; Mice; Mice, Inbred C57BL; Molecular Sequence Data; Myelin Proteolipid Protein; Myelin-Oligodendrocyte Glycoprotein; Nicotine; Peptide Fragments; T-Lymphocytes

Haptoglobin (HP) is an acute phase protein synthesized by liver cells in response to IL-6. HP has been demonstrated to modulate the immune response and to have anti-inflammatory activities. To analyze HP's effect on autoimmune inflammation, we here studied the course of EAE induced by immunization of Hp knockout (Hp(-/-)) and syngeneic WT mice with myelin oligodendrocyte glycoprotein peptide (MOG(35-55)). Hp(-/-)mice suffered from a more severe disease that was associated with increased expression of IL-17A, IL-6, and IFN-gamma mRNA in the CNS and with a denser cellular infiltrate in the spinal cord. During the recovery phase, a significantly higher number of myeloid DC, CD8+ cells, IL-17+ CD4+ and IFN-gamma+ CD4+ cells persisted in the CNS of Hp(-/-) mice. Absence of HP affected the priming and differentiation of T cells after MOG(35-55) immunization, as levels of Th2 cytokines produced in response to MOG stimulation by Hp(-/-) T cells were reduced. These results suggest that HP plays a modulatory and protective role on autoimmune inflammation of the CNS.

Topics: Animals; Autoimmune Diseases; Brain; Encephalomyelitis, Autoimmune, Experimental; Enzyme-Linked Immunosorbent Assay; Glycoproteins; Haptoglobins; Immunization; Immunoglobulin G; Inflammation; Interferon-gamma; Interleukin-10; Interleukin-17; Lymph Nodes; Mice; Mice, Inbred BALB C; Mice, Knockout; Myelin Proteins; Myelin-Associated Glycoprotein; Myelin-Oligodendrocyte Glycoprotein; Peptide Fragments; Reverse Transcriptase Polymerase Chain Reaction; Spinal Cord; Spleen; T-Lymphocytes; Th2 Cells; Transforming Growth Factor beta

Cholera toxin (CT), a major enterotoxin produced by Vibrio cholerae, elicits mucosal adjuvant activities by inducing antigen-specific CD4+ T cells secreting T helper type 2 (Th2) cytokines. Experimental autoimmune encephalomyelitis (EAE) is induced by Th1 cells specific for myelin-derived antigens. We induced EAE in C57BL/6 mice with myelin oligodendrocyte glycoprotein (MOG) 35-55 and CT was nasally administered as an immunomodulator on day 7 following MOG challenge. Clinical severity in the CT-treated mice was milder when compared to PBS-treated mice, while the levels of expression of interleukin (IL)-12 and interferon (IFN)-gamma in the central nervous system (CNS) of CT-treated mice were lower than PBS-treated mice. Thus, nasal administration of the mucosal immunomodulator CT ameliorated the severity of EAE, which was associated with the suppression of Th1 cell responses.

Topics: Adjuvants, Immunologic; Administration, Intranasal; Amino Acid Sequence; Animals; Autoimmune Diseases; Central Nervous System; Cholera Toxin; Drug Evaluation, Preclinical; Encephalomyelitis, Autoimmune, Experimental; Female; Glycoproteins; Humans; Interferon-gamma; Interleukin-12; Mice; Mice, Inbred C57BL; Myelin-Oligodendrocyte Glycoprotein; Peptide Fragments; Severity of Illness Index; Spleen; Th1 Cells; Th2 Cells