The clinical disease course of MS is classified according to the characteristics and severity of disease progression over time. The most common disease course of MS is Relapsing Remitting MS (RRMS). This disease course is characterized by a defined acute attack (increase in disability), which is followed by a full recovery and subsequent attacks over time. Secondary Progressive MS (SPMS) is similar to RRMS, but instead of full recovery during remission, residual deficit is maintained. SPMS is characterized by less recovery during remission following attacks and fewer attacks as the disease course switches from a relapsing remitting disease course to a more progressive disease course. Primary Progressive MS (PPMS) is a disease course characterized by a progressive increase in disability over time in the absence of well-defined relapses and/or remissions. Progressive Relapsing MS (PRMS) is the least common of the disease courses characterized by a progressive disability from the onset of disease, but contains clear relapses in disease severity in the absence or presence of full recovery. While the initiating antigen/epitope is not known in MS, a number of commonly shared CD4⁺ T cell epitopes have been identified, i.e., MBP_13–32, MBP_83–99, MBP_111–129, and MBP_146–170, MOG_1–20, MBP_35–55, and PLP_139–154. In contrast, animal models of MS have helped to identify putative mechanisms by which epitope spreading occurs. In R-EAE, the activation of the autoreactive CD4⁺ T cells that are specific for the initiating antigen epitope occurs in the draining lymph node. Also during the acute phase of disease the destruction of myelin allows for the release of both PLP and MBP. Due to antigen availability and CD4⁺ T cell precursor frequency, the activation of the secondary population of CD4⁺ T cell specific for PLP_178–191 occurs during the primary relapse, e.g., intramolecular spread epitope. In the case of R-EAE the activation of the spread epitope-specific CD4⁺ T cells is believed to occur within the CNS. During the secondary relapse, CD4⁺ T cells specific for MBP_84–104 are activated, e.g., intermolecular epitope spreading.

Signals delivered by the engagement of the TCR (signal 1) and costimulatory molecules (CD28; signal 2) induce different signaling pathways that result in the activation of multiple transcription factors. Ligation of the TCR by peptide–MHC on an APC triggers the recruitment of the TCR and signaling elements, e.g. phospholipase C-1 (PLC-1) for the Ca²⁺ influx–nuclear factor of activated T cells (NFAT) pathway and PKC- for the NF- B and AP-1 pathway, which control nuclear transcriptional and gene activation to lipid rafts. To induce differentiation to an IFN-γ producing Th1 cell, STAT4 activation coupled with NFAT activated by the TCR induces the expression of T-bet. In turn T-bet and NFAT induce the expression of IFN-γ. Current findings suggest that inhibition of PI3K, PKC, and PLC (in red) block CD80 induced increase in IFN-γ production. This supports the hypothesis that stimulation via CD80 on CD4⁺ T cells positively regulates effector Th1 function. Cross-linking CD80 on T cells induces an increase in the tyrosine phosphorylation of multiple intracellular proteins, and increases the level of IFN-γ and T-bet transcription. Findings indicate that cross-linking CD80 on CD4⁺ T cells activated in Th1-promoting conditions increases the level of IFN-γ produced by increasing the rate of IFN-γ transcription via the activation of a Ca²⁺-dependent signaling pathway.

Signals delivered by the engagement of the T-cell receptor (TCR; Signal 1) and co-stimulatory molecules (CD28; Signal 2) induce different signaling pathways that result in the activation of multiple transcription factors. Ligation of the TCR by peptide–MHC complexes triggers the recruitment of signaling molecules, such as phospholipase C-1 (PLC), which induces the Ca²⁺ influx, and nuclear factor of activated T-cells (NFAT) and protein kinase C-θ (PKCθ) that regulate the nuclear factor-κB (NF-κB) and activator protein-1 (AP1) pathway, respectively, which control nuclear transcriptional and gene activation. In the nucleus, NFAT cooperates with AP1 and other transcription factors to induce a program of gene expression, leading to interleukin-2 (IL-2) production. TCR engagement in the absence of co-stimulation results in the induction of NFAT proteins without concomitant AP1 activation. In the absence of cooperative binding to AP1 (FOS and JUN), NFAT regulates the transcription of a distinct set of anergy-inducing genes, such as Casitas B-lineage lymphoma B (CBL-B). Anergy-associated factors inhibit T-cell function at different levels leading to T-cell unresponsiveness.