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Torpedoing myasthenia gravis
Myasthenia gravis is an autoimmune disease characterized by muscular weakness due to the presence of Abs against the muscle nicotinic acetylcholine receptor (AChR). Studies in the animal model, experimental myasthenia gravis, indicate that IL-4 may have a protective function in the disease. On p. 604 , Ostlie et al. present a long term study of IL-4 deficiency on Torpedo AChR-induced experimental myasthenia gravis. They show that IL-4-/- B6 mice developed chronic self-reactive Ab and long lasting muscle weakness after a single immunization with Torpedo AchR. In contrast, more than one immunization was usually required to develop symptoms of experimental myasthenia gravis in IL-4+/+ mice, and the symptoms were of limited duration. In addition, anti-self AChR CD4+ T cells were present in the early phase of the response in IL-4-/- mice, whereas such cells were not detected in IL-4+/+ mice until late in the response, when they were recovering from the symptoms. Therefore, IL-4 appears to play a suppressive role in both the xenogenic response to the Torpedo AChR as well as the CD4+ T cell response to self-AchR. The authors postulate that IL-4 dependent regulatory Th3 cells may be involved in controlling experimental myasthenia gravis in IL-4+/+ mice.
Signaling changes in shape
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activity. This study identifies
p190RhoGEF as a mediator of CD40 signaling. The great calcium wave
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Death by estrogen
Researchers have long suspected that estrogen plays
a role in many autoimmune diseases, since women are affected much more
frequently than men. Monocytes and macrophages are important cells in
the inflammatory responses that often characterize autoimmune diseases;
it is also known that defects in apoptosis are involved in the
development of autoimmune diseases. In the study on p. 628
, Mor et al.
investigated the link between estrogen, monocytes/macrophages and the
Fas/Fas ligand system (the receptor/ligand pair most commonly
associated with apoptosis). Estrogen treatment increased Fas
ligand expression and induced apoptosis in monocytes, but not
in monocyte-differentiated macrophages. Two estrogen recognizing
elements were detected in the Fas ligand promoter: the estrogen
regulatory element, which binds the estrogen receptor and drives gene
expression, and an AP-1 motif. The authors also showed that estrogen
receptors 
and are differentially expressed in monocytes and
macrophages. Therefore, any evaluation of estrogen action must take
into account its influence on the Fas ligand promoter, as well as the
status of cell differentiation and the receptor isoform expressed in
the cell of study.
V.I.P.s
Vasoactive intestinal peptide is a neuropeptide
that is produced by both lymphoid and neural cells. It has a wide range
of immunological functions that are mediated through several different
receptors on various immunocompetent cells, including acting as a
potent anti-inflammatory agent. Voice et al. (p. 308
) present data
showing that vasoactive intestinal peptide is required for induction of
a Th2 phenotype in mice. Using transgenic mice constitutively
expressing VPAC2, the form of the receptor that is the dominant
transducer of vasoactive intestinal peptide on activated Th cells, and
VPAC2 knockout mice, they examined the influence of vasoactive
intestinal peptide on T cell phenotype. They found an elevated number
of IL-4 secreting CD4+ T cells following
stimulation of T cells from the VPAC2 transgenic mice. By eliminating
vasoactive intestinal peptide from cell cultures, the secretion of IL-4
and IL-10 decreased, while the secretion of IFN-
increased. T
lymphocyte derived vasoactive intestinal peptide thus appears to be a
major contributor to the skewing of Th cell responses.
"Bottoms-up" T cell signaling
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First line of defense
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-defensin-2 was greatly enhanced by
cross-talk between keratinocytes and LPS-stimulated monocyte-derived
cells. The increase in human -defensin-2 was relatively selective,
with most other genes being repressed, and was mediated by IL-1
secreted by the monocyte-derived cells. It thus appears that both IL-1
and human -defensin-2 have important roles in the host defense
reaction of the epidermis, expanding our understanding of how
infections may be prevented following skin injury. Regulating recombination
Is T cell lineage determination simply dependent on
expression of appropriate TCRs or is it dependent on other
developmental programs? Understanding how TCR gene recombination is
regulated in the context of the developing T cell is important in
addressing this question. V(D)J recombination occurs only between pairs
of gene segments that are flanked by a 12- and 23-bp spacer (12/23
rule). However, V to DJ rearrangement at the TCR locus is subject to
additional restrictions beyond the 12/23 rule. On p. 5
, Tillman et al.
examine the mechanistic basis of the "beyond 12/23" restrictions on
V(D)J recombination. They use extrachromosomal substrates to show that
the preference of V for D rather than J occurs at the level of
DNA cleavage, requires no lymphoid specific components other than
recombinase activating gene (RAG) proteins, and appears to depend on
the relative strengths of the D as compared to the J
recombination signal sequences (RSSs), rather than a specific
requirement for V/D RSS synapsis. They establish that the precise
sequence of RAG recognition sites flanking TCR gene segments is the
major factor in restricting V to DJ rearrangement.
Related articles in The JI:
to D Rearrangement by RSSs Can Be Mediated by the V(D)J Recombinase in the Absence of Additional Lymphoid-Specific Factors
-Synuclein
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