Antibodies against glutamic acid decarboxylase in intravenous immunoglobulin preparations can affect the diagnosis of type 1 diabetes mellitus.

BACKGROUND AND OBJECTIVES: Intravenous immunoglobulins (IVIgs) contain various autoantibodies, including those against glutamic acid decarboxylase (GADAb), a valuable biomarker of type 1 diabetes mellitus. Passive transfer of GADAb from IVIgs to patients poses a risk of misdiagnosis, and information on the specific titres of GADAb and their impact on diagnostic accuracy remains limited. This study aimed to provide further insights into the origin of GADAb detected in patient serum following IVIg infusion. MATERIALS AND METHODS: GADAb titres in IVIg products from Japan and the United States were measured using enzyme-linked immunosorbent assay-based assays. For reliable quantification, GADAb titres in pooled plasma were quantified and compared with those in the IVIg products. The determined titres were used to estimate the likelihood of passively detecting acquired GADAb in individuals receiving IVIgs. RESULTS: GADAbs were prevalent in IVIg products; however, the titres varied significantly among different lots and products. Importantly, IVIg-derived GADAb was estimated to remain detectable in patient serum for up to 100 days following a dosage of 2000 mg/kg. CONCLUSION: Clinicians should consider that IVIg preparations may contain GADAb, which can lead to false-positive results in serological assays. Careful interpretation of the assay results is key to the definitive diagnosis of type 1 diabetes mellitus.

Autoantibody profiles in intravenous immunoglobulin preparations: A possible cause of mistaken autoimmunity diagnosis.

BACKGROUND: Intravenous immunoglobulins (IVIgs) derived from the pooled plasma of thousands of donors contain numerous types of IgG molecules, including autoantibodies commonly used to diagnose autoimmunity. While these autoantibodies can cause misinterpretation of serological tests for IVIg recipients, their profiles in IVIg preparations are not fully understood. STUDY DESIGN AND METHODS: Using binding-capability based immune assays, we measured 18 varieties of clinically relevant autoantibodies in domestic blood donor-derived IVIg products. In addition, we analyzed an IVIg product from a US brand to evaluate the influence of regional and racial differences. Based on the determined autoantibody titers, pharmacokinetics of passively acquired autoantibodies and their possible detection period in serum were estimated. RESULTS: Anti-thyroglobulin (Tg), anti-thyroidperoxidase (TPO), and anti-Sjögren's-syndrome-related antigen A (SS-A) antibodies were present in considerable amounts in IVIg products. Notably, these three autoantibodies can be detected in IVIg recipients' sera for up to 3 months after infusion. DISCUSSION: To the best of our knowledge, this is the first study that analyzed multiple autoantibody profiles in both pooled plasma and IVIg products and that further evaluated their potential influences on diagnosis of autoimmunity. Clinicians should keep in mind that IVIgs contain several autoantibodies and that their infusion can produce false-positive serology results. To establish an accurate diagnosis, serological tests must be carefully interpreted and clinical symptoms should be more purposefully considered if patients are receiving IVIg therapy.

Alterations in inter-alpha inhibitor protein expression after hypoxic-ischemic brain injury in neonatal rats.

Hypoxic-ischemic (HI) brain injury is frequently associated with premature and/or full-term birth-related complications that reflect widespread damage to cerebral cortical structures. Inflammation has been implicated in the long-term evolution and severity of HI brain injury. Inter-Alpha Inhibitor Proteins (IAIPs) are immune modulator proteins that are reduced in systemic neonatal inflammatory states. We have shown that endogenous IAIPs are present in neurons, astrocytes and microglia and that exogenous treatment with human plasma purified IAIPs decreases neuronal injury and improves behavioral outcomes in neonatal rats with HI brain injury. In addition, we have shown that endogenous IAIPs are reduced in the brain of the ovine fetus shortly after ischemic injury. However, the effect of HI on changes in circulating and endogenous brain IAIPs has not been examined in neonatal rats. In the current study, we examined changes in endogenous IAIPs in the systemic circulation and brain of neonatal rats after exposure to HI brain injury. Postnatal day 7 rats were exposed to right carotid artery ligation and 8% oxygen for 2h. Sera were obtained immediately, 3, 12, 24, and 48h and brains 3 and 24h after HI. IAIPs levels were determined by a competitive enzyme-linked immunosorbent assay (ELISA) in sera and by Western immunoblots in cerebral cortices. Serum IAIPs were decreased 3h after HI and remained lower than in non-ischemic rats up to 7days after HI. IAIP expression increased in the ipsilateral cerebral cortices 24h after HI brain injury and in the hypoxic contralateral cortices. However, 3h after hypoxia alone the 250kDa IAIP moiety was reduced in the contralateral cortices. We speculate that changes in endogenous IAIPs levels in blood and brain represent constituents of endogenous anti-inflammatory neuroprotective mechanism(s) after HI in neonatal rats.

Intravenous Immunoglobulin Suppresses Abortion Relates to an Increase in the CD44bright NK Subset in Recurrent Pregnancy Loss Model Mice.

Recurrent pregnancy loss (RPL), which mostly is of unknown etiology (unexplained RPL, uRPL), is defined as three or more consecutive spontaneous abortions. Some women with uRPL display a higher fraction and cytotoxicity of natural killer (NK) cells in the periphery and endometrium. Therefore, some uRPL cases have been explained by autoimmune abnormalities. The efficacy of intravenous immunoglobulin (IVIg) for uRPL has been confirmed in several clinical trials; however, its mechanism remains unknown, mainly because the abortion mechanism remains to be elucidated. In the present study, we analyzed the mechanisms of both abortion and IVIg action using a uRPL mouse model in which abortion was induced by lipopolysaccharide injection. IVIg attenuated the abortion rate in the uRPL model mice. The suppressive effect of IVIg was maximized by high dose administration early after lipopolysaccharide injection. Specifically, we discovered the presence of two distinct uterine NK (uNK) subsets: CD44(bright) and CD44(mid) In uRPL model mice, we observed an increase in the number of CD44(bright) uNK cells, while the CD44(mid) uNK subset remained unchanged. Furthermore, when abortion was reduced by IVIg administration, the cell number of the CD44(bright) uNK subset did not increase, which might allow differentiating pathological from normal uNK cells based on CD44 expression. Based on these results, we propose not only an effective administration protocol of IVIg to the uRPL model mice, but also a novel mechanism of abortion related to the increase in the CD44(bright) subset and of IVIg, which suppresses the increase of the CD44(bright) subset.

Multiple Bowen's disease in a patient with a history of possible arsenic exposure: a case report.

A 81-year-old man with a patch of scaly erythema on his scrotum visited Hiratsuka Kyosai Hospital in June 2006. Reddish, scaly plaques, which were untreated, were present on his back and lower legs since 1999. Pathological examination of the lesions on the scrotum revealed Bowen's disease; therefore he was referred to our clinic for further treatment. During his visit Tokai University Hospital, irregularly bordered scaly erythematous patches were observed on his back, left arm, right knee, and right foot, sizing from 2 to 4 cm in diameter. He was treated with phenol and liquid nitrogen cryotherapy; however, he dropped out of clinic after receiving treatment for a year. At this point, most lesions were cured and only scars remained. In June 2009, he revisited Tokai University Hospital, and this time, multiple scaly erythematous patches were noted on his back and both the arms and legs. The results of the biopsies of 4 lesions obtained from the back, right arm, right knee, and the right foot led to the diagnosis of multiple Bowens' disease. During the inquiry, we learned that since birth, he has resided in Hiratsuka City and had often used water from wells. We researched the possibilities of water and soil contaminations in the Hiratsuka area.

Early lesion of palisaded neutrophilic granulomatous dermatitis in ulcerative colitis.

Palisaded neutrophilic granulomatous dermatitis (PNGD) is a rare clinical entity of unknown cause. It often coexists with various autoimmune or immunoreactive systemic diseases, and thus it has been reported under multiple names. We describe a patient with quiescent ulcerative colitis, who presented with recurrent small tender papules, nodules and erythematous plaques, located mainly on her hands, together with finger swelling and polyarthralgia. The histopathologic picture indicated an early stage of PNGD with focal degeneration of collagen fibers but without distinct granuloma formation. The differentiation from neutrophilic dermatoses was necessary because of dense and diffuse infiltration of neutrophils with leukocytoclastic debris throughout the dermis, and the association of ulcerative colitis. Dapsone monotherapy was effective in improving the clinical symptoms. PNGD is only rarely associated with ulcerative colitis, and this case suggests that the concept of PNGD, especially in its early stages, might be considered in the wide spectrum of neutrophilic dermatoses.