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Biomedical subjects

Pamela A McCombe

Publications and source records attributed to Pamela A McCombe.

9 recordsLinked to original sources
PubMed2006

Studies of HLA associations in male and female patients with Guillain-Barré syndrome (GBS) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP).

HLA associations are found to differ with the gender of the patient in some autoimmune diseases. Here we have investigated whether there are gender-related HLA associations in Guillain-Barré syndrome (GBS) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), both of which occur more frequently in male patients than in females. In GBS, no particular HLA associations were noted, except for a slight negative association in both males and females for carriage of HLA-DR5. In CIDP, the gene frequency and the frequency of individuals positive for HLA-DR2 were greater in female patients than female controls, although this was statistically significant only for the gene frequency. Furthermore more female CIDP patients were homozygous for DR2, than male CIDP patients, or male or female controls and patients with GBS. This suggests that sex-related factors may interact with the risk associated with carriage of HLA-DR2 for development of CIDP.

DNA Mutational Analysis↗
PubMed2006

Motor unit number estimation--a Bayesian approach.

All muscle contractions are dependent on the functioning of motor units. In diseases such as amyotrophic lateral sclerosis (ALS), progressive loss of motor units leads to gradual paralysis. A major difficulty in the search for a treatment for these diseases has been the lack of a reliable measure of disease progression. One possible measure would be an estimate of the number of surviving motor units. Despite over 30 years of motor unit number estimation (MUNE), all proposed methods have been met with practical and theoretical objections. Our aim is to develop a method of MUNE that overcomes these objections. We record the compound muscle action potential (CMAP) from a selected muscle in response to a graded electrical stimulation applied to the nerve. As the stimulus increases, the threshold of each motor unit is exceeded, and the size of the CMAP increases until a maximum response is obtained. However, the threshold potential required to excite an axon is not a precise value but fluctuates over a small range leading to probabilistic activation of motor units in response to a given stimulus. When the threshold ranges of motor units overlap, there may be alternation where the number of motor units that fire in response to the stimulus is variable. This means that increments in the value of the CMAP correspond to the firing of different combinations of motor units. At a fixed stimulus, variability in the CMAP, measured as variance, can be used to conduct MUNE using the "statistical" or the "Poisson" method. However, this method relies on the assumptions that the numbers of motor units that are firing probabilistically have the Poisson distribution and that all single motor unit action potentials (MUAP) have a fixed and identical size. These assumptions are not necessarily correct. We propose to develop a Bayesian statistical methodology to analyze electrophysiological data to provide an estimate of motor unit numbers. Our method of MUNE incorporates the variability of the threshold, the variability between and within single MUAPs, and baseline variability. Our model not only gives the most probable number of motor units but also provides information about both the population of units and individual units. We use Markov chain Monte Carlo to obtain information about the characteristics of individual motor units and about the population of motor units and the Bayesian information criterion for MUNE. We test our method of MUNE on three subjects. Our method provides a reproducible estimate for a patient with stable but severe ALS. In a serial study, we demonstrate a decline in the number of motor unit numbers with a patient with rapidly advancing disease. Finally, with our last patient, we show that our method has the capacity to estimate a larger number of motor units.

Action Potentials↗
PubMed2005

Increased circulating T cell reactivity to GM1 ganglioside in patients with Guillain-Barré syndrome.

This study was performed to determine whether increased ganglioside-specific T cell reactivity can be detected in the peripheral blood of patients with Guillain-Barre syndrome (GBS) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). T cell responsiveness to the gangliosides GM1, GM3, GD1a, GD1b, GD3, GT1b, GQ1b and sulphatide was assessed in peripheral blood mononuclear cells from untreated GBS patients (57), CIDP patients (43), patients with other peripheral neuropathies (55) and healthy control subjects (74) in a standard 6-day proliferation assay. Increased T cell reactivity to GM1 occurred in GBS patients compared to healthy controls and patients with other neuropathies. There was increased reactivity to GM3 in GBS patients compared to patients with other neuropathies but not compared to healthy controls. The frequencies of increased T cell reactivity to GM1 and GM3 in CIDP patients were intermediate between those of GBS patients and controls. We suggest that T cell reactivity to gangliosides might play a contributory role in the pathogenesis of GBS and perhaps CIDP.

Adolescent↗
PubMed2004

Effect of gender on T-cell proliferative responses to myelin proteolipid protein antigens in patients with multiple sclerosis and controls.

Multiple sclerosis (MS) is an inflammatory demyelinating disorder of the central nervous system. Gender influences both susceptibility to MS, with the disease being more common in women, and the clinical course of disease, with an increased proportion of males developing the primary progressive form of the disease. The basis for these differences may include genetic and immunological factors, and the immunological differences between men and women may be influenced by the effects of the sex hormones. Over several years we have collected blood from MS patients and controls, and measured T-cell responses to myelin proteolipid protein (PLP) and myelin basic protein (MBP) and have shown increased responses to PLP in MS patients compared to healthy controls and patients with other neurological diseases. In the present study we analyzed data from over 500 individuals, to determine whether there are differences between males and females in their responses to PLP and MBP. We found that there was higher frequency of increased T-cell reactivity to immunodominant PLP peptides in women than in men, particularly in non-MS individuals. We suggest that this may be relevant to the higher prevalence of MS in women.

Amino Acid Sequence↗
PubMed2003

Early pregnancy factor suppresses the infiltration of lymphocytes and macrophages in the spinal cord of rats during experimental autoimmune encephalomyelitis but has no effect on apoptosis.

Early pregnancy factor (EPF) is a secreted protein with immunosuppressive and growth factor properties that has been shown to suppress acute experimental autoimmune encephalomyelitis (EAE) induced with myelin basic protein (MBP) in Lewis rats. EAE is associated with infiltration of the central nervous system (CNS) with inflammatory cells. Spontaneous recovery involves the loss of T lymphocytes from the CNS and the selective apoptosis of Vbeta8.2+ cells. In the present study, T cell, macrophage (CD11b/c+) and B cell (CD45RA+) populations in spinal cord and popliteal lymph nodes (LN) of Lewis rats with EAE were quantitated and apoptosis was studied. Rats were treated with EPF or vehicle. Following treatment on day 14 after inoculation with MBP, neither 1 x 100 microg nor 2 x 100 microg doses of EPF affected the total number of cells infiltrating the spinal cord on day 15, although the higher dose caused a decrease in the number of CD5+ and CD11b/c+ cells. Treatment with 2 x 100 microg/day from days 10 to 14 decreased the total number of infiltrating cells, and the numbers of CD5+, CD11b/c+ and CD45RA+ cells. Apoptosis was unaffected. No alteration on the number or type of inflammatory cells in the popliteal LN was observed after treatment on days 10-14. However, treatment with EPF from days 0 to 11 increased the total number of T and B cells and CD5+ T cells found on day 12 in the LN. Similarly, there was an increase in the frequency of MBP-reactive cells in the LN as determined by limiting dilution analysis. These results suggest that EPF treatment reduces the numbers of lymphocytes and macrophages in the CNS, possibly through an effect on cell trafficking.

Animals↗
PubMed2003

Early pregnancy factor treatment suppresses the inflammatory response and adhesion molecule expression in the spinal cord of SJL/J mice with experimental autoimmune encephalomyelitis and the delayed-type hypersensitivity reaction to trinitrochlorobenzene in normal BALB/c mice.

Early pregnancy factor (EPF) is a secreted protein, present in serum during early pregnancy and essential for maintaining viability of the embryo. It is a homologue of chaperonin 10 (Cpn10) but, unlike Cpn10, it has an extracellular role. EPF has immunosuppressive and growth regulatory properties. Previously we have reported the preparation of recombinant EPF (rEPF) and shown that treatment with rEPF will suppress clinical signs of MBP-EAE in Lewis rats and PLP-EAE in SJL/J mice. In the present study, these findings have been extended to investigate possible mechanisms involved in the action of EPF. Following treatment of mice with rEPF from the day of inoculation, there were fewer infiltrating CD3+ and CD4+ cells in the parenchyma of the spinal cord during the onset of disease and after the initial episode, compared with mice treated with vehicle. Expression of the integrins LFA-1, VLA-4 and Mac-1 and of members of the immunoglobulin superfamily of adhesion molecules ICAM-1 and VCAM-1 was suppressed in the central nervous system (CNS) following rEPF treatment. The expression of PECAM-1 was not affected. To determine if rEPF suppressed T cell activation in the periphery, the delayed-type hypersensitivity (DTH) reaction of normal BALB/c mice to trinitrochlorobenzene (TNCB) following treatment with rEPF was studied. The results showed that treatment with rEPF suppressed the DTH reaction, demonstrating the ability of EPF to downregulate the cell-mediated immune response. These results indicate that suppression of immunological mechanisms by rEPF plays a major role in the reduction of clinical signs of disease in experimental autoimmune encephalomyelitis (EAE).

Animals↗
PubMed2003

Increased circulating T cell reactivity to GM3 and GQ1b gangliosides in primary progressive multiple sclerosis.

We have previously shown that patients with primary progressive multiple sclerosis (MS) have significantly elevated plasma levels of antibody to GM3 ganglioside compared to patients with relapsing-remitting MS, healthy subjects and patients with other neurological diseases. Anti-GM3 antibody levels were elevated also in patients with secondary progressive MS but to a lesser extent than in primary progressive MS. As gangliosides are particularly enriched in the axonal membrane, these findings suggested that antiganglioside immune responses might contribute to the axonal damage in progressive forms of MS. The present study was performed to determine whether peripheral blood T cell responses to GM3 are also increased in progressive MS. Blood was collected from 98 untreated patients with MS (40 with relapsing-remitting, 27 with secondary progressive and 31 with primary progressive MS), 50 healthy subjects and 24 patients with other disorders of the CNS, and reactivity to GM1, GM3, GD1a, GD1b, GD3, GT1b, GQ1b and sulphatide was assessed by 6-day T cell proliferation assays. Increased T cell reactivity to GM3 and GQ1b occurred significantly more often in patients with primary progressive MS than in healthy subjects and patients with other CNS diseases. These findings suggest that ganglioside-specific T cells may contribute to the axonal damage in primary progressive MS.

Adult↗
PubMed1998

The roles of Fas, Fas ligand and Bcl-2 in T cell apoptosis in the central nervous system in experimental autoimmune encephalomyelitis.

The selective apoptotic elimination of autoreactive T cells in the central nervous system (CNS) contributes to the resolution of inflammation and the spontaneous clinical recovery from experimental autoimmune encephalomyelitis (EAE). To assess the molecular mechanisms involved in this process, we used three-colour flow cytometry to examine the expression of apoptosis-regulating proteins by inflammatory cells isolated from the spinal cords of Lewis rats immunized with myelin basic protein (MBP) and complete Freund's adjuvant. Throughout the course of the disease, which peaked 12-14 days after inoculation and was followed by clinical recovery, we analyzed the DNA content of the spinal cord inflammatory cells to assess apoptosis and, simultaneously, we measured the expression of five proteins (Fas, Fas ligand (Fas-L), Bcl-2, Bcl-x and Bax) which modulate the apoptotic process. Cells expressing the death effector molecules Fas and Fas-L were particularly prone to undergo apoptosis, and were over-represented in the apoptotic population. Of the cells expressing the cell death inhibitor Bcl-2, a low proportion were undergoing apoptosis compared to the proportion of the total inflammatory cell population undergoing apoptosis, indicating that expression of Bcl-2 protects against T cell apoptosis in this disease. There was no evidence, however, that the apoptotic regulators Bcl-x and Bax influenced the susceptibility to apoptosis. We also found that Vbeta8.2+ T cells, which constitute the predominant encephalitogenic MBP-reactive T cell population in the Lewis rat, have a high frequency of Fas and Fas-L expression compared to other inflammatory cells. This would account for the previously demonstrated susceptibility of Vbeta8.2+ T cells to apoptosis in the CNS in EAE. These findings support the hypothesis that autoreactive T cells are eliminated from the CNS during spontaneous recovery from EAE by activation-induced apoptosis involving the Fas pathway.

Animals↗