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Multiple Sclerosis (MS) is an immune-mediated, demyelinating disorder of the CNS. Glatiramer acetate (GA/Copaxone) is an FDA-approved treatment for relapsing-remitting MS that induces functional changes in antigen-presenting cells (APC) and CD4 and CD8 T-cells. We have previously shown that treatment-naïve MS patients have deficient CD8 T-cell responses to GA, which are restored after GA therapy. This is associated with enhanced cytotoxic/suppressive function in these cells. In this study, we assessed the immediate immunologic changes induced by GA therapy in treatment-naïve MS patients by multiparametric monitoring of T-cell and APC subsets prior to and at 4, 12, 24, 72 hrs of treatment. In untreated healthy control subjects quantitative and functional readouts showed stable dynamics over time. MS patients showed greater proportions of memory/effector CD4 and CD8 populations at baseline, which did not vary. Similarly, cytokine production by APC subsets was also stable. Interestingly, as early as 4 to 12 hrs after the initial GA injection, we observed significantly enhanced suppressive ability in CD8 T-cells. This rapid functional change consistently occurred in GA, as well as an IFN-b-treated control cohort. These studies show that the induction of T-cell suppressive function is an important early event during therapy. Future studies will delineate whether these changes are predictive of sustained longterm immunologic and clinical responsiveness.

Multiple Sclerosis (MS) is the leading disease of the central nervous system and a significant, costly cause of disability in young adults. Patients at risk for MS often present with a single demyelinating event, typically called a “clinically isolated syndrome” (CIS). A CIS can occur in the brain, spinal cord (Acute Partial Transverse Myelitis, APTM), or optic nerve (Optic Neuritis, ON) at similar rates and present a challenging diagnostic and therapeutic dilemma. Stratifying CIS patients most likely to develop MS is a complicated process, but desirable since treatment with the appropriate immunomodulatory agents early in the disease course can delay long-term disability. Thus, a primary focus of our laboratory has been to develop a completely novel type of biomarker that can identify CIS patients that will develop MS. This unique biomarker is based on a pattern of antibody gene mutations (i.e. antibody gene signature or “AGS”) that is exclusive to B cells from the cerebrospinal fluid and brain lesions of MS patients that initially presented with either TM or ON. In fact, the AGS is consistently elevated in patients with one attack of ON that go on to develop definite MS, and can predict conversion to MS with 91% accuracy. More recently, we are testing the hypothesis that the AGS serves as a predictor for conversion to MS in CIS patients that present with TM. Preliminary data demonstrate that the AGS is also prevalent in CIS patients presenting with TM.

Recent evidence suggests that B and T cell interactions may be paramount in relapsing remitting multiple sclerosis (RRMS) disease pathogenesis. We hypothesized that memory B cell pools from RRMS patients may specifically harbor a subset of potent neuro-antigen presenting cells that support neuro-antigen reactive T cell expansion and activation. To assess the potential influence of neuro-antigen specific memory B cells from RRMS patients on autologous CD4+ T cell activation, we compared CD80 and HLA-DR expression, IL-10 and LTα secretion, neuro-antigen binding capacity, and functional neuro-antigen presentation by memory B cells from RRMS patients and compared these parameters to naïve B cells from RRMS patients and to memory and naïve B cells from healthy donors (HDs). We identified memory B cells from a subset of RRMS patients that were functionally capable of presenting neuro-antigen to autologous T cells. Notwithstanding the fact that the phenotypic parameters that promote efficient antigen presentation were observed to be similar between RRMS and HDs memory B cells, a corresponding capability to present neuro-antigen was not observed in HD memory B cells. Our results demonstrate for the first time that the memory B cell pool in RRMS harbors neuro-antigen specific clones that can activate T cells.

The following problem has created interest in various high schools and even in some colleges. The proof presented here is designed to give the serious student of plane geometry some insight into techniques that can be used in other originals.

The law of cosines has always frustrated those teachers who wish to use it computationally. The transformation developed in this paper makes it more amenable to the use of logarithmic computation.

(9) Several boundary agreements were found by all three approaches. All of them isolated certain heavy industry areas, a few residential neighborhoods, and some large outlying sectors. (10) The social and demographic techniques also singled out small, highly homogeneous, and distinctive areas of the city which were concealed by the ecological approach. For example, Figure 4 shows a segment of the city which is completely enclosed by rivers, railroads, factories, and main thoroughfares. The boundaries indicated by the demographic and social indices do not correspond to the ecological ones. Further, this area is not internally homogeneous from other points of view. Two types of demographic areas have boundaries which at places coincide, fall within, and extend beyond the ecological boundaries. The same applies for two types of social intimacy which lie across the area in question. Obviously compromises among the boundaries were necessary to arrive at a satisfactory general sub-area plan for the city. Since no one of the three plans was satisfactory in every way to meet census tract requirements, they were all used in making the eventual plan. How the compromises were made will be reported elsewhere.