Neutralization of muscarinic receptor autoantibodies by intravenous immunoglobulin in Sjögren syndrome.

Autoantibodies that inhibit M3 muscarinic receptor (M3R)-mediated neurotransmission and cause bladder and bowel dysfunction have been reported in patients with Sjögren syndrome and belong to a family of functional autoantibodies that includes the thyroid-stimulating hormone receptor antibody present in Graves disease. We have recently reported that antiidiotypic antibodies present in pooled immunoglobulin (Ig) G or IgG from healthy individuals neutralize anti-M3R antibody-mediated inhibition of smooth muscle contraction in vitro. Here we extend these studies to the clinic by examining whether therapeutic doses of intravenous immunoglobulin (IVIG) provided to patients with autoimmune diseases neutralize anti-M3R activity in vivo and improve bladder and bowel symptoms.

Passive transfer of Sjogren's syndrome IgG produces the pathophysiology of overactive bladder.

Objective: The presence, in patients with primary and secondary Sjogren's syndrome (SS), of autoantibodies that acutely inhibit M(3) muscarinic receptor (M3R)-mediated bladder contractions is difficult to reconcile with the fact that symptoms of detrusor overactivity and other features of cholinergic hyperresponsiveness occur in this disease. This study was undertaken to examine the in vivo effects of these autoantibodies on bladder function by examining bladder responsiveness and compliance following passive transfer of patient IgG to mice.

Methods: Contractile responses of isolated bladder strips both to the muscarinic agonist carbachol and to electrically evoked acetylcholine release were measured 48 hours after injection of mice with patient or control IgG.

Antiidiotypic antibodies neutralize autoantibodies that inhibit cholinergic neurotransmission.

Objective: Functional autoantibodies that inhibit M(3) muscarinic receptor (M3R)-mediated neurotransmission have been reported in patients with Sjögren's syndrome (SS) and in patients with scleroderma. Because of limited reports that intravenous immunoglobulin (IVIG) improves dysautonomia in primary SS, we investigated whether IVIG neutralizes the effect of anti-M3R antibodies on colon smooth muscle contractions, in an in vitro functional assay.

Methods: IgG obtained from patients with primary SS, patients with rheumatoid arthritis and secondary SS, and patients with scleroderma was tested, before and after coincubation with equimolar amounts of IVIG or its F(ab')(2) and Fc fractions, for the ability to inhibit carbachol-evoked colon smooth muscle contractions.

Tolerance through indifference: autoreactive B cells to the nuclear antigen La show no evidence of tolerance in a transgenic model.

Systemic autoimmune diseases are characterized by the production of high titer autoantibodies specific for ubiquitous nuclear self-Ags such as DNA, Sm, and La (SS-B), so the normal mechanisms of B cell tolerance to disease-associated nuclear Ags have been of great interest. Mechanisms of B cell tolerance include deletion, anergy, developmental arrest, receptor editing, and B cell differentiation to the B-1 subtype. However, recent studies in our laboratory have suggested that B cell tolerance to the nuclear autoantigen La is limited in normal mice, and tolerance may reside primarily in the T cell compartment.

Vasoactive intestinal peptide binding autoantibodies in autoimmune humans and mice.

Autoantibodies capable of binding the immunoregulatory neuropeptide vasoactive intestinal peptide (VIP) were detected in the sera of a mouse strain prone to autoimmune disease due to the lpr mutation (MRL/lpr). The autoantibodies were not present in control wildtype MRL/lpr mice, but they were readily detected in humans without autoimmune disease. The binding was due to low affinity VIP recognition.

Anti-La/SSB antibodies transported across the placenta bind apoptotic cells in fetal organs targeted in neonatal lupus.

Objective: To determine whether La and/or Ro epitopes on apoptotic cells in fetal organs that are targeted in neonatal lupus syndrome (NLS) are accessible for binding by autoantibodies in vivo, we traced the fate of transplacental autoantibodies in a murine passive transfer model.

Methods: Pregnant mice at day 15 of gestation (E15) were injected intraperitoneally with human anti-Ro/La-positive sera or control sera, and transplacental transfer of human autoantibodies was tested by enzyme-linked immunosorbent assay with recombinant antigens. Multiple cryostat sections at the level of the heart of E17 fetuses were visualized simultaneously for human IgG binding and apoptosis (TUNEL) under confocal microscopy.

Association of BAFF/BLyS overexpression and altered B cell differentiation with Sjögren's syndrome.

BAFF (BLyS, TALL-1, THANK, zTNF4) is a member of the TNF superfamily that specifically regulates B lymphocyte proliferation and survival. Mice transgenic (Tg) for BAFF develop an autoimmune condition similar to systemic lupus erythematosus. We now demonstrate that BAFF Tg mice, as they age, develop a secondary pathology reminiscent of Sjögren's syndrome (SS), which is manifested by severe sialadenitis, decreased saliva production, and destruction of submaxillary glands.