HIGH LEVELS OF MYELIN ANTIGEN AUTOREACTIVE T CELL RESPONSES IN BLOOD AND CEREBROSPINAL FLUID IN PATIENTS WITH ALZHEIMER'S DISEASE

The participation of immune mechanisms in the pathogenesis of dementia of Alzheimer type (AD) has been suggested. We examined T cell responses to myelin basic protein (MBP) and myelin proteolipid protein (PLP) using an enzyme linked immunospot (ELISPOT) assay by enumerating mononuclear cells (MNC) that in blood and cerebrospinal fluid (CSF) secreted the cytokine interferon γ (IFN γ) spontaneously and after short time culture of the cells in presence of MBP or PLP. These myelin components are supposed to induce autoaggressive immunity in multiple sclerosis. MBP and PLP reactive IFN γ secreting cells were detected in patients with AD and, for comparison, in patients with other non inflammatory neurological diseases(OND) and patients with tension type headache (TH). Elevated levels of MBP and PLP reactive IFN γ secreting cells were found in blood in AD patients compared to OND and TH, such cells in AD patients were further enriched in CSF. Levels of MBP reactive as well as spontaneously IFN γ secreting cells in CSF were about 180 fold and 250 fold higher than in blood of AD patients, and also higher than the corresponding data in OND(30 fold and 20 fold) and in TH (120 fold and 20 fold). It is unclear whether the autoreactive T cell responses to MBP and PLP, especially accumulated in CSF, have any importance for the pathogenesis of AD.

Homeostasis and regulation of autoreactive B cells

In contrast to the previous belief that autoreactive B cells are eliminated from the normal repertoire of B cells,many autoreactive B cells actually escape clonal deletion and develop into mature B cells.These autoreactive B cells in healthy individuals perform some beneficial functions in the host and are homeostatically regulated by regulatory T and B cells or other mechanisms to prevent autoimmune diseases.Autoreactive B-1 cells constitutively produce polyreactive natural antibodies for tissue homeostasis.Recently,autoreactive follicular B cells were reported to participate actively in the germinal center reaction.Furthermore,the selection and usefulness of autoreactive marginal zone(MZ)B cells found in autoimmune diseases are not well understood,although the repertoire of MZ B-cell receptors(BCRs)is presumed to be biased to detect bacterial antigens.In this review,we discuss the autoreactive B-cell populations among all three major B-cell subsets and their regulation in immune responses and diseases.

Etiopathogenesis of primary biliary cirrhosis

Primary biliary cirrhosis(PBC) is an autoimmune disease of the liver characterized by progressive bile duct destruction eventually leading to cirrhosis and liver failure.The serological hallmark of the disease is the presence of circulating antimitochondrial antibodies(AMA).These reflect the presence of autoreactive T and B cells to the culprit antigens,the E2 subunits of mitochondrial 2-oxo-acid dehydrogenase enzymes,chiefly pyruvate dehydrogenase(PDC-E2).The disease results from a combination of genetic and environmental risk factors.Genetic predisposition is indicated by the higher familial incidence of the disease particularly among siblings and the high concordance rate among monozygotic twins.Environmental triggering events appear crucial to disrupt a pre-existing unstable immune tolerance of genetic origin allowing,after a long latency,the emergence of clinical disease.Initiating mimetopes of the vulnerable epitope of the PDC-E2 autoantigen can be derived from microbes that utilize the PDC enzyme or,alternatively,environmental xenobiotics/chemical compounds that modify the structure of native proteins to make them immunogenic.A further alternative as a source of antigen is PDC-E2 derived from apoptotic cells.In the effector phase the biliary ductular cell,by reason of itsproclivity to express the antigen PDC-E2 in the course of apoptosis,undergoes a multilineage immune attack comprised of CD4+ and CD8+ T cells and antibody.In this article,we critically review the available evidence on etiopathogenesis of PBC and present interpretations of complex data,new developments and theories,and nominate directions for future research.

Inducible resistance to Fas-mediated apoptosis in B cells

Apoptosis produced in B cells through Fas (APO-1, CD95) triggering is regulated by signals derived from other surface receptors: CD40 engagement produces upregulation of Fas expres. sion and marked susceptibility to Fas-induced cell death, whereas antigen receptor engagement, or IL-4R engagement, inhibits Fas killing and in so doing induces a state of Fas-resistance, even in otherwise sensitive, CD40-stimulated targets. Surfaceim. munoglobulin and IL-4R utilize at least partially distinct pathways to produce Fas-resistance that differentially depend on PKC and STAT6, respectively. Further, surface immunoglob- "lin signaling for inducible Fas-resistance bypasses Bib, requires NF-GB, and entails new macromolecular synthesis. Terminal effectors of B cell Fas-resistance include the known anti-apoptotic gene products, Bcl-xL and FLIP, and a novel anti-apoptotic gene that encodes FAIM (Fas Apoptosis Inhibitory Molecule). faim was identified by differential display and exists in two alternatively spliced forms; maim-S is broadly expressed, but faim-L expression is tissue-specific. The FAIM sequence is highly evolu tionarily conserved, suggesting an important role for this molecule throughout phylogeny. Inducible resistance to Fas killing is hypothesized to protect foreign antigen-specific B cells during potentially hazardous interactions with FasL-bearing T cells, whereas autoreactive B cells fail to become Fas-resistant and are deleted via Fas-dependent cytotoxicity. Inadvertent or aberrant acquisition of Fas-resistance may permit autoreactive B cells to escape Fas deletion, and malignant lymphocytes to impede anti-tumor immunity.

Two distinct subpopulations of marginal zone B cells exhibit differential antibody-producing capacities and radioresistance

Marginal zone(MZ)B cells,which are splenic innate-like B cells that rapidly secrete antibodies(Abs)against blood-borne pathogens,are composed of heterogeneous subpopulations.Here,we showed that MZ B cells can be divided into two distinct subpopulations according to their CD80 expression levels.CD80^(high)MZ B cells exhibited greater Ab-producing,proliferative,and IL-10-secreting capacities than did CD80^(low)MZ B cells.Notably,CD80^(high)MZ B cells survived 2-Gy whole-body irradiation,whereas CD80^(low)MZ B cells were depleted by irradiation and then repleted with one month after irradiation.Depletion of CD80^(low)MZ B cells led to accelerated development of type II collagen(CII)-induced arthritis upon immunization with bovine CII.CD80^(high)MZ B cells exhibited higher expression of genes involved in proliferation,plasma cell differentiation,and the antioxidant response.CD80^(high)MZ B cells expressed more autoreactive B cell receptors(BCRs)that recognized double-stranded DNA or CII,expressed more immunoglobulin heavy chain sequences with shorter complementarity-determining region 3 sequences,and included more clonotypes with no N-nucleotides or with B-1a BCR sequences than CD80^(low)MZ B cells.Adoptive transfer experiments showed that CD21^(+)CD23^(+)transitional 2 MZ precursors preferentially generated CD80^(low)MZ B cells and that a proportion of CD80^(low)MZ B cells were converted into CD80^(high)MZ B cells;in contrast,CD80^(high)MZ B cells stably remained CD80^(high)MZ B cells.In summary,MZ B cells can be divided into two subpopulations according to their CD80 expression levels,Ab-producing capacity,radioresistance,and autoreactivity,and these findings may suggest a hierarchical composition of MZ B cells with differential stability and BCR specificity.

A mouse model of vitiligo based on endogenous auto-reactive CD8+T cell targeting skin melanocyte

Vitiligo is the most common human skin depigmenting disorder.It is mediated by endogenous autoreactive CD8+T cells that destruct skin melanocytes.This disease has an estimated prevalence of 1%of the global population and cur-rently has no cure.Animal models are indispensable tools for understanding vitiligo pathogenesis and for developing new therapies.Here,we describe a vitiligo mouse model which recapitulates key clinical features of vitiligo,including epidermis depigmentation,CD8+T cell infiltration in skin,and melanocyte loss.To activate endogenous autoreactive cytotoxic CD8+T cells targeting melanocytes,this model relies on transient inoculation of B16F10 melanoma cells and depletion of CD4+regulatory T cells.At cellular level,epidermal CD8+T cell infiltration and melanocyte loss start as early as Day 19 after treatment.Visually apparent epidermis depigmentation occurs 2 months later.This protocol can efficiently induce vitiligo in any C57BL/6 background mouse strain,using only commercially available reagents.This enables researchers to carry out in-depth in vivo vitiligo studies utilizing mouse genetics tools,and provides a powerful platform for drug discovery.