LatY136F knock-in mouse model for human IgG4-related disease.

BACKGROUND: The adaptor protein Linker for activation of T cell (LAT) is a key signaling hub used by the T cell antigen receptor. Mutant mice expressing loss-of-function mutations affecting LAT and including a mutation in which tyrosine 136 is replaced by a phenylalanine (LatY136F) develop lymphoproliferative disorder involving T helper type 2 effector cells capable of triggering a massive polyclonal B cell activation that leads to hypergammaglobulinemia G1 and E and to non-resolving inflammation and autoimmunity. The purpose of this study was to evaluate whether the phenotypes of LatY136F knock-in mice resemble the immunohistopathological features of immunoglobulin G4-related disease (IgG4-RD). METHODS: LatY136F knock-in mice were sacrificed at 4-20 weeks of age, and pancreas, kidney, salivary gland and lung were obtained. All organs were stained with hematoxylin-eosin and with Azan for estimation of collagen in fibrosis, and the severity scores of inflammation and fibrosis were evaluated. Immunostainings were performed to analyze the types of infiltrating cells. In addition, the effects of corticosteroid treatment on the development of tissue lesions and serum levels of IgG1 were assessed. RESULTS: Tissue lesions characterized by inflammatory mononuclear cell infiltration and fibrosis were detected in pancreas, kidney, and salivary gland starting from 6 weeks of age. Immunostainings showed pronounced infiltration of plasma cells, CD4-positive T cells, and macrophages. Infiltrating plasma cells predominantly expressed IgG1. The extent of inflammation in pancreas and salivary glands was markedly reduced by corticosteroid treatment. CONCLUSIONS: LatY136F knock-in mice displayed increased production of Th2-type IgG1 (a homologue of human IgG4) and developed multiple organ tissue lesions reminiscent of those seen in patients with IgG4-RD. Moreover, the development of these tissue lesions was highly sensitive to corticosteroid treatment like in IgG4-RD. For these reasons we consider the LatY136F knock-in mouse strain to represent a promising model for human IgG4-RD.

Analysis of IgG4-positive clones in affected organs of IgG4-related disease.

OBJECTIVE: We investigated class switch reaction (CSR) in affected organs and evaluated whether the same or genetically related clones exist in IgG4-RD. METHODS: We studied three patients with IgG4-RD. Total cellular RNA was extracted from salivary glands and peripheral blood and lung tissue. Activation-induced cytidine deaminase (AID) and immunoglobulin heavy chain third complementarity determining region (IgVH-CDR3) of IgM and IgG4 were detected by reverse transcription polymerase chain reaction (RT-PCR). We analyzed the clonal relationship of infiltrating IgG4-positive cells, as compared with IgM. We determined the existence of common clones among organs and patients. RESULT: AID was expressed in salivary glands of all patients and lung tissue in one. Closely related IgVH-CDR3 sequences in infiltrating IgG4-positive cells were detected in salivary glands and lung tissue. Identical IgVH-CDR3 sequence between IgM and IgG4 in salivary glands was detected in one patient, indicating CSR in salivary glands. Identical IgVH-CDR3 sequences of IgG4-positive cells were detected between salivary glands and peripheral blood in two patients. Four identical sequences of IgVH-CDR3 existed between patients. Interestingly, one of the four sequences was detected in all patients. CONCLUSION: Our results demonstrate the existence of common antigen(s) shared by patients with IgG4-RD.

[Study on Reduction of Radiation Exposure by Using Carbon Dioxide Angiography Catheter in Vascular Access Intervention Therapy(VAIVT)].

In vascular access intervention therapy (VAIVT), carbon dioxide is used as negative contrast medium for patients with iodine allergy or for those who have vascular access but not started with dialysis yet and have not endangered their remaining kidney function. To capture the movement of jet-injected carbon dioxide during the carbon dioxide angiography, we performed imaging at a rate of 15 frames per second. This method has a higher level of radiation exposure than angiography using an iodine contrast medium. Therefore we developed a catheter with 20 helical side holes in the tip (carbon dioxide angiography catheter), which allows large numbers of tiny bubbles to be generated simultaneously. In our study, we evaluate whether the use of this catheter can reduce the number of frames taken per second thus reducing the radiation exposure. A comparative experiment with existing angiography catheters with no side holes suggested that the use of this carbon dioxide angiography catheter to be useful for reducing the radiation exposure to patients and operators. Moreover, angiography using this catheter is highly useful from viewpoint of improving the stenotic vesselvisibility and reducing the side effects of using carbon dioxide, and we expect that the carbon dioxide angiography method is effective for patients and operators.

Situs inversus and cystic kidney disease: Two adult patients with this Heterogeneous syndrome.

BACKGROUND: Situs inversus is a rare complication of cystic kidney diseases. Only three genes, INVS (NPHP2), NPHP3 and PKD2 have been proved to be responsible for some cases, while the responsible genes in many others are still unknown. CASE REPORTS: Here we report two male patients with situs inversus combined with cystic kidney disease without any family history of polycystic kidney disease. Their renal function was normal in childhood but culminated in end stage renal disease in middle age. No pathogenic mutations were found in mutation analysis of INVS, IFT88, PKD2, UMOD or NPHP3 in them. CONCLUSIONS: Past reported cases of situs inversus and cystic kidney diseases were divided into three groups, i.e., gestational lethal renal dysplasia group, infantile or juvenile nephronophthisis group and polycystic kidney disease group. The present patients are different from each of these groups. Moreover, the renal lesions of the present two cases are quite different from each other, with one showing mildly atrophic kidneys with small numbers of cysts and the other an enlarged polycystic kidney disease, suggesting very heterogeneous entities.

A case of refractory cutaneous polyarteritis nodosa in a patient with hepatitis B carrier status successfully treated with tumor necrosis factor alpha blockade.

We describe a patient with refractory cutaneous polyarteritis nodosa (CPAN) with hepatitis B virus (HBV) carrier status who was successfully treated with tumor necrosis factor alpha (TNF-α) blockade, using etanercept, and we review 5 similar cases. We administered etanercept because of the occurrence of repeated flares despite aggressive therapy. C-reactive protein normalization; prednisolone dose-sparing; and absence of any adverse events, including HBV reactivation with nucleotide analogue administration, or renal dysfunction, have been achieved for 8 months. TNF-α blockade should be considered for intractable CPAN.

Investigations of IgG4-related disease involving the skin.

OBJECTIVES: IgG4-related skin disease is not widely recognized. This prompted us to investigate the clinical and pathological features of five patients we encountered with IgG4-related disease (IgG4-RD) affecting the skin. METHODS: We investigated the clinical and pathological features of these five patients, including the distribution, onset, and morphology of eruptions, their pathological and immunohistochemical characteristics, and the occurrence of disease in other organs. RESULTS: The skin lesions were typically erythematous nodules and papules and brown papules like prurigo nodularis, which developed on the face or in the head and neck areas in four patients. Skin lesions were the first clinical manifestation in three patients. All five patients had sialadenitis and/or dacryoadenitis. The mean serum IgG4 concentration was 665.6 ± 410.0 mg/dl. Infiltrations of IgG4-positive plasma cells were observed in both the dermis and subcutaneous tissue. Germinal center formations were seen in three patients. Mild to moderate fibrosis was observed in all patients, and focal obliterative phlebitis in one. The average count of IgG4-positive cells was 67.3/high-power field (23.0-128.6). Wide variation in the numbers of infiltrating IgG4-positive cells was noted. CONCLUSION: IgG4-RD appears to have a distinctive clinicopathological presentation in the skin, differentiating it from other cutaneous disorders.

IgG4-related skin lesions in a patient with IgG4-related chronic sclerosing dacryoadenitis and sialoadenitis.

We describe a 60-year-old man with IgG4-related chronic sclerosing dacryoadenitis and sialoadenitis associated with lymphoplasmacytic and eosinophilic infiltration in erythematous nodules. Physical examination revealed left eye extrusion and small itchy nodules on the scalp and neck. The serum IgG level was 1,570 mg/dL, IgG4 463 mg/dL (29.5%), and IgE 4,554 IU/mL. Lacrimal gland biopsy disclosed prominent infiltrates of IgG4-positive plasma cells and scattered eosinophilic infiltrates with fibrosis, consistent with IgG4-related disease. A skin biopsy of a cutaneous nodule demonstrated that the infiltrated plasma cells around arterioles or venules in the deep dermis and subcutaneous fat tissue were strongly positive for IgG4. Although the swollen lacrimal and parotid gland and itchy subcutaneous erythematous nodules improved rapidly with oral prednisolone at a dose of 20 mg per day, the skin, lacrimal, and parotid lesions deteriorated simultaneously during steroid tapering and improved after increasing the dosage. As skin lesions are easy to biopsy, further study of the skin manifestations of IgG4-related disease will be important in further clarifying the clinical spectrum, pathophysiology and response to therapy of this disorder.

IgG4-related tubulointerstitial nephritis and hepatic inflammatory pseudotumor without hypocomplementemia.

Immunoglobulin G4 (IgG4)-related tubulointerstitial nephritis (TIN) is often accompanied by autoimmune pancreatitis (AIP) or chronic sclerosing dacryoadenitis and sialoadenitis. However, IgG4-related TIN without AIP or lacrimal and/or salivary gland lesions has not been well recognized. Here, we report a case of IgG4-related TIN associated with hepatic inflammatory pseudotumor without AIP or lacrimal and/or salivary gland lesions. A 58-year-old Japanese man with epigastralgia underwent contrast-enhanced computed tomography (CT), which revealed multiple low-density lesions in both kidneys and a low density hepatic mass. Laboratory tests showed an extremely high level of serum IgG4. Percutaneous renal and hepatic biopsies showed diffuse infiltration of lymphocytes and IgG4-positive plasma cells with fibrosis in both tissues. Two months after administration of oral prednisolone, both lesions decreased in size on follow-up CT, and the serum creatinine level also improved. No recurrence has been detected for two years with a maintenance dose of prednisolone.

[Visualization of stenosis in vascular access by bubble method under carbon dioxide (CO2) angiographic procedures].

A percutaneous transvascular angioplasty (PTA) is performed to relieve failed vascular access for hemodialysis. Angiography using non-ionic iodinated contrast media is the imaging modality of choice for performing PTA. However, the use of iodinated contrast media is contraindicated for patients with a history of iodine allergy. Since 1920, carbon dioxide (CO(2)) has been used as a safe contrast medium in various studies. In CO(2) shunt angiography for hemodialysis, visualization of the vascular structures was often suboptimal due to shunt-specific conditions, such as rapid flow and narrow diameter of the vessels. In the present report, we attempted an improvement of the visualization by injection of CO(2) bubbles in view of the properties of CO(2) (floating and low viscosity). The results indicated that the CO(2) bubbles angiography clearly demonstrated the narrow vessels and stenotic portions that were not visualized by conventional CO(2) angiography. In addition, the required volume of CO(2) could be reduced in comparison with previous studies in the literature. Therefore, the method seemed to be effective in reducing exposure and preventing complication by CO(2). Thus, CO(2) bubbles angiography may be useful for shunt angiography and sequential angioplasty when experiencing shunt problems.

Apparent diffusion coefficient map based on diffusion-weighted magnetic resonance imaging is useful in diagnosing the brainstem variant of reversible posterior leukoencephalopathy syndrome with uremia.

A 54-year-old Japanese man entered our hospital for investigation of appetite loss. His blood pressure was 201/113 mmHg, and laboratory findings revealed renal failure and hyponatremia. On physical examination, disorientation and dysarthria were observed. Hemodialysis was performed the same day. Magnetic resonance imaging (MRI) after hemodialysis revealed swelling of the brainstem and a high signal intensity on fluid-attenuated inversion recovery (FLAIR) imaging, similar to findings of central pontine myelinolysis (CPM), which is generally irreversible. However, on an apparent diffusion coefficient (ADC) map based on diffusion-weighted MRI, higher signal intensity was observed in the area of the high signal intensity on FLAIR imaging, which is not seen in CPM. The abnormal neurological symptoms improved within a few days, and MRI findings also normalized. We diagnosed the lesion as the brainstem variant of reversible posterior leukoencephalopathy syndrome (RPLS) with uremia. ADC map was very useful in diagnosing RPLS with uremia.

Impact of inflow reduction of arteriovenous fistula on systemic hemodynamics in a patient with high-output heart failure during hemodialysis: A case report.

A 68-year-old woman was admitted with dyspnea. The patient had been treated with hemodialysis for renal failure for 11 years. On admission, chest X-ray showed pulmonary edema. Right-heart catheterization revealed high cardiac output (11.8 l/min) and elevated pulmonary capillary wedge pressure (PCWP). Doppler ultrasonography showed high-flow of an arteriovenous fistula (AVF) for hemodialysis. The patient was diagnosed as having high-output heart failure due to a high-flow AVF. Inflow reduction of the AVF was performed by proximal radial artery ligation. Right-heart catheterization performed 2 weeks after the operation revealed that cardiac output had decreased from 11.8 to 9.5 l/min and PCWP was also reduced from 21 to 9 mmHg. Furthermore, flow of the AVF measured by Doppler ultrasonography was also decreased. To our knowledge, this is the first report that assessed hemodynamics of high-output heart failure before and after inflow reduction of the AVF by repeated right-heart catheterization.

A case of immunoglobulin G4-related chronic sclerosing sialadenitis and dacryoadenitis associated with tuberculosis.

We describe a 64-year-old woman with chronic sclerosing sialadenitis and dacryoadenitis, which developed during treatment for cervical lymph node tuberculosis. Anti-tuberculosis treatment did not improve the swelling in the lacrimal and submandibular glands, and a biopsy specimen of the lacrimal gland showed inflammation, with abundant lymphoid follicles with fibrosis and granuloma without caseous necrosis. Immunohistological examination of a repeat biopsy specimen showed abundant immunoglobulin (Ig) G4-positive plasma cell infiltration. Corticosteroid therapy improved the salivary gland swelling without reactivation of the tuberculosis. This case suggests that an abnormal immunological reaction to tuberculosis may be one of the etiological candidates for IgG4-related disease.

Systemic capillary leak syndrome associated with compartment syndrome.

Systemic capillary leak syndrome is characterized by recurrent hypovolemic shock attributable to increased systemic capillary leakage. A 26-year-old woman was admitted because of recurrent episodes of hypovolemic shock. Hemoconcentration, hypoalbuminemia, and monoclonal gammopathy were observed. We diagnosed systemic capillary leak syndrome. Three years later, she again had an attack of systemic capillary leak syndrome complicated with pretibial compartment syndrome. This case emphasizes the importance of muscle compartment pressure monitoring during volume resuscitation in patients with systemic capillary leak syndrome.