Judith M. Greer

An altered peptide ligand mediates immune deviation and prevents autoimmune encephalomyelitis.

In experimental autoimmune encephalomyelitis (EAE) induced with myelin proteolipid protein (PLP) peptide 139-151, we have previously shown that the disease is mediated by Th1 cells, which recognize tryptophan 144 as the primary TCR contact point. Here we describe an altered peptide ligand (APL), generated by a single amino acid substitution (tryptophan to glutamine) at position 144 (Q144), which inhibits the development of EAE induced with the native PLP 139-151 peptide (W144). We show that the APL induces T cells that are cross-reactive with the native peptide and that these cells produce Th2 (IL-4 and IL-10) and Th0 (IFN gamma and IL-10) cytokines. Adoptive transfer of T cell lines generated with the APL confer protection from EAE. These data show that changing a single amino acid in an antigenic peptide can significantly influence T cell differentiation and suggest that immune deviation may be one of the mechanisms by which APLs can inhibit an autoimmune disease.

Immune dysregulation and self-reactivity in schizophrenia: do some cases of schizophrenia have an autoimmune basis?

Schizophrenia affects 1% of the worlds population, but its cause remains obscure. Numerous theories have been proposed regarding the cause of schizophrenia, ranging from developmental or neurodegenerative processes or neurotransmitter abnormalities to infectious or autoimmune processes. In this review, findings suggestive of immune dysregulation and reactivity to self in patients with schizophrenia are examined with reference to criteria for defining whether or not a human disease is autoimmune in origin. Associations with other autoimmune diseases and particular MHC haplotypes, increased serum levels of autoantibodies, and in vivo and in vitro replication of some of the functional and ultrastructural abnormalities of schizophrenia by transfer of autoantibodies from the sera of patients with schizophrenia suggest that, in some patients at least, autoimmune mechanisms could play a role in the development of disease. Recent findings regarding specific autoimmune responses directed against neurotransmitter receptors in the brain in patients with schizophrenia will also be reviewed.

Sexual Dimorphism in Autoimmune Disease

We briefly survey the concept of autoimmunity and nominate the range of autoimmune diseases that include multisystemic and organ-specific disorders, and cite prevalences of autoimmune diseases in males and females, in humans and in experimental animals. Most human autoimmune diseases such as systemic lupus erythematosus (SLE), multiple sclerosis (MS) and autoimmune thyroid disease, have an increased incidence and prevalence in females, but a few others such as autoimmune diabetes, the Guillain Barré syndrome (GBS) and psoriasis are increased in males. Animal models of autoimmunity show an equivalent sexual dimorphism. The possible reasons for the differing incidence and prevalence of autoimmune diseases in females and males engage our attention. Environmental exposures may differ for females and males. There are innate differences in the function of the female and male immune systems, and there is some evidence for differences between females and males in the ability of a target organ for autoimmunity to withstand damage. In seeking reasons for these differences, we review the role of sex hormones in immunity and include results of trials of hormone therapy in autoimmune diseases. The association of autoimmunity and pregnancy, a female-specific condition, is discussed, and the claimed effects of lymphoid cell microchimerism on provocation of autoimmunity are reviewed. Genetic predisposition is an important factor in autoimmune disease and we particularly focus on genes on the X and Y chromosomes, the role of X chromosome inactivation, and the interaction of the sex of the patient with other genetic factors. The possible role of epigenetic mechanisms, including environmental influences, is then surveyed. We assert that sex is a vital variable that must be considered in all immunological studies, as it should be at all levels of biological research.

The effect of ageing on human lymphocyte subsets: comparison of males and females

BackgroundThere is reported to be a decline in immune function and an alteration in the frequency of circulating lymphocytes with advancing age. There are also differences in ageing and lifespan between males and females. We performed this study to see if there were differences between males and females in the frequency of the different lymphocyte subsets with age.ResultsUsing flow cytometry we have examined different populations of peripheral blood leukocytes purified from healthy subjects with age ranging from the third to the tenth decade. We used linear regression analysis to determine if there is a linear relationship between age and cell frequencies. For the whole group, we find that with age there is a significant decline in the percentage of naïve T cells and CD8+ T cells, and an increase in the percentage of effector memory cells, CD4+foxp3+ T cells and NK cells. For all cells where there was an effect of ageing, the slope of the curve was greater for men than for women and this was statistically significant for CD8+αβ+ T cells and CD3+CD45RA-CCR7- effector memory cells. There was also a difference for naïve cells but this was not significant.ConclusionThe cause of the change in percentage of lymphocyte subsets with age, and the different effects on males and females is not fully understood but warrants further study.

Role of gender in multiple sclerosis: clinical effects and potential molecular mechanisms.

Multiple sclerosis (MS) is more prevalent in females than males, and this female predominance is increasing as time goes by. Additionally, gender appears to play critical roles in development, progression and treatment of MS, and is therefore an aspect that should always be considered in the design and interpretation of research and clinical trials for MS. In this review, factors that could potentially explain the gender-biased observations in MS are discussed. These include sex-specific differences between the male and female immune systems and nervous systems, genetic and epigenetic or environmental-related effects, the effects of gonadal hormones, and materno-fetal interactions.

Identification of the di-pyridyl ketone isonicotinoyl hydrazone (PKIH) analogues as potent iron chelators and anti-tumour agents.

In an attempt to develop chelators as potent anti‐tumour agents, we synthesized two series of novel ligands based on the very active 2‐pyridylcarboxaldehyde isonicotinoyl hydrazone (PCIH) group. Since lipophilicity and membrane permeability play a critical role in Fe chelation efficacy, the aldehyde moiety of the PCIH series, namely 2‐pyridylcarboxaldehyde, was replaced with the more lipophilic 2‐quinolinecarboxaldehyde or di‐2‐pyridylketone moieties. These compounds were then systematically condensed with the same group of acid hydrazides to yield ligands based on 2‐quinolinecarboxaldehyde isonicotinoyl hydrazone (QCIH) and di‐2‐pyridylketone isonicotinoyl hydrazone (PKIH). To examine chelator efficacy, we assessed their effects on proliferation, Fe uptake, Fe efflux, the expression of cell cycle control molecules, iron‐regulatory protein‐RNA‐binding activity, and 3H‐thymidine, 3H‐uridine and 3H‐leucine incorporation. Despite the high lipophilicity of the QCIH ligands and the fact that they have the same Fe‐binding site as the PCIH series, surprisingly none of these compounds were effective. In contrast, the PKIH analogues showed marked anti‐proliferative activity and Fe chelation efficacy. Indeed, the ability of these ligands to inhibit proliferation and DNA synthesis was similar or exceeded that found for the highly cytotoxic chelator, 311. In contrast to the PCIH and QCIH analogues, most of the PKIH group markedly increased the mRNA levels of molecules vital for cell cycle arrest. In conclusion, our studies identify structural features useful in the design of chelators with high anti‐proliferative activity. We have identified a novel class of ligands that are potent Fe chelators and inhibitors of DNA synthesis, and which deserve further investigation.

Myelin proteolipid protein - the first 50 years

Myelin proteolipid protein (PLP), the most abundant protein of central nervous system (CNS) myelin, is a hydrophobic integral membrane protein. Because of its physical properties, which make it difficult to work with, progress towards determining the exact function(s) and disease associations of myelin PLP has been slow. However, recent molecular biology advances have given new life to investigations of PLP, and suggest that it has multiple functions within myelin and is of importance in several neurological disorders.

Surges of Increased T Cell Reactivity to an Encephalitogenic Region of Myelin Proteolipid Protein Occur More Often in Patients with Multiple Sclerosis Than in Healthy Subjects

We have previously shown that patients with multiple sclerosis (MS) have increased T cell responses to the immunodominant region (residues 184–209) of myelin proteolipid protein (PLP). The present study investigated whether this reactivity fluctuates over time and correlates with disease activity. We performed monthly limiting dilution assays for 12–16 mo in four healthy subjects and five patients with relapsing-remitting MS to quantify the frequencies of circulating T cells proliferating in response to PLP41–58, PLP184–199, PLP190–209, myelin basic protein (MBP), MBP82–100, and tetanus toxoid. Disease activity was monitored by clinical assessment and gadolinium-enhanced magnetic resonance imaging of the brain. There were fluctuations in the frequencies of autoreactive T cells in all subjects. Compared with healthy controls, MS patients had significantly more frequent surges of T cells reactive to the 184–209 region of PLP, but infrequent surges of T cell reactivity to MBP82–100. There was temporal clustering of the surges of T cell reactivity to MBP82–100 and MBP, suggesting T cell activation by environmental stimuli. Some clinical relapses were preceded by surges of T cell reactivity to PLP184–209, and in one patient there was significant correlation between the frequency of T cells reactive to PLP184–199 and the total number of gadolinium-enhancing magnetic resonance imaging lesions. However, other relapses were not associated with surges of T cell reactivity to the Ags tested. T cells reactive to PLP184–209 may contribute to the development of some of the CNS lesions in MS.

Minireview: Autoimmune responses to myelin proteolipid protein

The authors present a brief historical sketch of the development of our understanding of immune responses to myelin proteolipid protein (PLP) and the acceptance of PLP as a potent antigen in the induction of experimental allergic encephalomyelitis (EAE). The distinct characteristics of the PLP molecule that may contribute to complex immune responses to this protein are reviewed and these responses are compared with those to MBP, both in the pathology of EAE and at the level of the T cell. Recent evidence demonstrating differences between T cell responses to PLP and MBP is reviewed. Finally, the potential contribution of immune responses to PLP in human diseases, particularly mutiple sclerosis (MS), that have been identified to date are then summarized.For the authors to write a review on PLP and its role in EAE without Marjorie is like their sailing a ship without a captain, compass or rudder. This review is largely based on work and ideas generated in Marjories laboratory, but it was prepared without her input. Consequently, it lacks her meticulous reflection on the structure of each of its sentences and on the use of each word. Papers written with Marjorie are usually honed to near perfection late into the evening at her kitchen table in Newton, where food, ideas, and warmth abound, and where her very patient and accommodating husband Sidney and a demanding but lovable canine are close at hand. Writing this essay gave the authors a chance to recognize our scientific forebears, to consider where we are at this point and to contemplate our future directions in studying immune responses to PLP. We are, indeed, very grateful and indebted to Marjorie for her generous personal and scientific support, wise guidance, inspiration, strength, energy and, most importantly, friendship. Marjorie, we thank you, you are our role model, and we affectionately anticipate many more years of continued collaboration with you.

Immune activation in the peripheral blood of patients with acute ischemic stroke.

Lymphocytes, neutrophils and macrophages are found in the brain in areas of acute ischaemic stroke. There is also evidence of modulation of systemic immune function after stroke, with post-stroke immunosuppression being observed. Because lymphocytes are activated in the peripheral immune compartment, before entry to the target organ, we reasoned that activated lymphocytes would be present in the circulation, prior to entering the brain, in patients after stroke. Because immune responses are controlled by regulatory mechanisms, we also reasoned that the post-stroke immunosuppression would involve T regulatory cells. The aim of the study was to look for evidence of immune activation and alterations in regulatory T cells in the peripheral blood of patients after acute ischaemic stroke, in comparison to age-matched healthy controls and patients with other neurological diseases (OND), and to determine the phenotype of the activated cells. The percentages of total and activated T cells, B cells, monocyte/ macrophages, and NK/NK-T cells were determined by labelling peripheral blood leukocytes with specific cell surface markers and analysis with 4-colour flow cytometry. The percentages of activated T cells and regulatory T cells were significantly increased in patients with ischemic stroke compared to healthy subjects and patients with OND. There was also an increase in the percentage of CCR7+ T cells. There were no significant differences in the activation of other cell types. In conclusion, there is evidence of immune activation and Treg cells in acute ischaemic stroke.