Differential transcriptomics in sarcoidosis lung and lymph node granulomas with comparisons to pathogen-specific granulomas.

RATIONALE: Despite the availability of multi-"omics" strategies, insights into the etiology and pathogenesis of sarcoidosis have been elusive. This is partly due to the lack of reliable preclinical models and a paucity of validated biomarkers. As granulomas are a key feature of sarcoidosis, we speculate that direct genomic interrogation of sarcoid tissues, may lead to identification of dysregulated gene pathways or biomarker signatures. OBJECTIVE: To facilitate the development sarcoidosis genomic biomarkers by gene expression profiling of sarcoidosis granulomas in lung and lymph node tissues (most commonly affected organs) and comparison to infectious granulomas (coccidiodomycosis and tuberculosis). METHODS: Transcriptomic profiles of immune-related gene from micro-dissected sarcoidosis granulomas within lung and mediastinal lymph node tissues and compared to infectious granulomas from paraffin-embedded blocks. Differentially-expressed genes (DEGs) were profiled, compared among the three granulomatous diseases and analyzed for functional enrichment pathways. RESULTS: Despite histologic similarities, DEGs and pathway enrichment markedly differed in sarcoidosis granulomas from lymph nodes and lung. Lymph nodes showed a clear immunological response, whereas a structural regenerative response was observed in lung. Sarcoidosis granuloma gene expression data corroborated previously reported genomic biomarkers (STAB1, HBEGF, and NOTCH4), excluded others and identified new genomic markers present in lung and lymph nodes, ADAMTS1, NPR1 and CXCL2. Comparisons between sarcoidosis and pathogen granulomas identified pathway divergences and commonalities at gene expression level. CONCLUSION: These findings suggest the importance of tissue and disease-specificity evaluation when exploring sarcoidosis genomic markers. This relevant translational information in sarcoidosis and other two histopathological similar infections provides meaningful specific genomic-derived biomarkers for sarcoidosis diagnosis and prognosis.

Neorickettsia helminthoeca associated lymphoid, enteric, and pulmonary lesions in dogs from Southern Brazil: An immunohistochemical study.

Neorickettsia helminthoeca (NH), the agent of salmon poisoning disease or canine neorickettiosis (CN), is a bacterial endosymbiont of the nematode Nanophyetus salmincola, and infections are spreading among specific fish-eating mammalians. This article describes the pathologic and immunohistochemical findings associated with spontaneous NH-induced infections in dogs from Southern Brazil. The principal pathologic findings were hypertrophy of Peyer patches and lymphadenopathy with lymphocytic proliferation, chronic interstitial pneumonia, and chronic enteritis associated with positive intralesional immunoreactivity to antigens of NH within macrophages and histiocytes. Positive immunoreactivity against canine parvovirus-2 (CPV-2) or/and canine distemper virus was not detected in the evaluated intestinal segments or in the samples from the cerebellum and lungs, respectively, from the dogs evaluated. These findings demonstrated that NH was involved in the enteric, pulmonary, and lymphoid lesions herein described, and provide additional information to confirm the occurrence of this bacterial endosymbiont within this geographical location. It is proposed that chronic pneumonia should be considered as a pathologic manifestation of NH-induced infections. Additionally, our results show that the occurrences of CN seem to be underdiagnosed in Southern Brazil due to the confusion with the incidence of CPV-2.

Nonproliferative and Proliferative Lesions of the Rat and Mouse Hematolymphoid System.

The INHAND Project (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice) is a joint initiative of the Societies of Toxicologic Pathology from Europe (ESTP), Great Britain (BSTP), Japan (JSTP), and North America (STP) to develop an internationally accepted nomenclature for proliferative and nonproliferative changes in rats and mice. The purpose of this publication is to provide a standardized nomenclature for classifying changes observed in the hematolymphoid organs, including the bone marrow, thymus, spleen, lymph nodes, mucosa-associated lymphoid tissues, and other lymphoid tissues (serosa-associated lymphoid clusters and tertiary lymphoid structures) with color photomicrographs illustrating examples of the lesions. Sources of material included histopathology databases from government, academia, and industrial laboratories throughout the world. Content includes spontaneous lesions as well as lesions induced by exposure to test materials. The nomenclature for these organs is divided into 3 terminologies: descriptive, conventional, and enhanced. Three terms are listed for each diagnosis. The rationale for this approach and guidance for its application to toxicologic pathology are described in detail below.

Lymphocutaneous nocardiosis in a kidney transplant patient successfully treated with tigecycline.

Cutaneous nocardiosis is an infrequent infection which has been increasingly reported in immunocompromised patients. Although trimethoprim-sulfamethoxazole is considered to be the agent of choice for treatment of nocardiosis, newer antimicrobials such as tigecycline have been proven to be effective in vitro, as well. We report the first case of primary cutaneous nocardiosis in a renal transplant recipient having corresponded well to treatment with tigecycline.

Flow immunophenotyping of benign lymph nodes sampled by FNA: Representative with diagnostic pitfalls.

BACKGROUND: Fine-needle aspiration with flow cytometry (FNA-FC) is routinely used in the evaluation of lymph nodes suspicious for lymphoma, yet data comparing immunophenotype distributions and outliers in benign lymph nodes sampled by fine-needle aspiration (FNA) versus excision are lacking. METHODS: Flow cytometry data from 289 benign lymph node FNA cases were assessed for the overall antigen distribution, with a focus on outliers relevant to the diagnosis of lymphoma. Distributions and outlier proportions were compared with those of a separate cohort of 298 excisional biopsies. RESULTS: Compared with excisional biopsies, FNA specimens overrepresented CD3+ events (72% vs 63%), underrepresented CD19+ events (22% vs 29%), and had 25% fewer large cell-gated events. Normalized antigen distributions in FNA were equivalent to those in excisional biopsy. Twenty-three percent of FNA-FC cases exhibited an outlier, including a skewed kappa:lambda light-chain ratio, increased CD5+ or CD10+ B-cell events, a skewed CD4:CD8 ratio, and increased CD7 loss on T cells, with no significant differences in frequency or type in comparison with excisional specimens. Outliers for the light-chain ratio and T-cell antigens were enriched among older patients and included patients with a variety of autoimmune/rheumatologic conditions. CONCLUSIONS: Benign lymph node FNA yields flow immunophenotypes remarkably similar to those from excisional biopsies. Outlier flow immunophenotypes are identified in benign lymph nodes sampled by FNA at a frequency similar to that with excisional biopsies. Older patients, who have a higher baseline risk of lymphoma, are more likely to exhibit lymphoma-mimicking outliers such as a light-chain predominance on B cells and skewed CD4:CD8 ratios or increased CD7 loss on T cells, and they warrant additional diagnostic caution.

Possible relationship between fibrosis of IgG4-related thymitis and the profibrotic cytokines, transforming growth factor beta 1, interleukin 1 beta and interferon gamma: a case report.

BACKGROUND: IgG4-related disease often forms a mass and the affected lesion is clinically removed because the mass cannot be differentiated from a neoplasm. Affected lesions commonly occur in the pancreas, hepatobiliary tract, kidney, and retroperitoneum. However, the lesion rarely occurs in the thymus. A histological worldwide consensus of IgG4-related disease proposed that pathological diagnosis of IgG4-related disease should meet more than two of three major features: 1) dense lymphoplasmacytic infiltration with greater than 40% IgG4+/IgG+ plasma cells, 2) storiform fibrosis; and 3) obliterative phlebitis. Currently, fibrosis of IgG4-related disease is thought to be induced by profibrotic cytokines such as transforming growth factor beta 1 (TGFB1), interleukin 1 beta (IL1B) and interferon gamma (IFNG), which are secreted by regulatory T cells (Tregs) and CD4-positive cytotoxic T cells. However, it is unclear whether profibrotic cytokines are associated with the fibrosis seen in IgG4-related thymitis. Here we examined whether cytokines in the mass were increased compared with those in the surrounding thymus, and whether Tregs were present in the mass, using reverse transcription absolute quantitative polymerase chain reaction (RT-ab-qPCR) and immunohistochemistry. CASE PRESENTATION: A 70-year-old Japanese man contracted IgG4-letated thymitis. Histological and immunohistochemical analyses demonstrated his mass had massive fibrosis with a focally storiform pattern and lymphoplasmacytic infiltration with 40% IgG4+/IgG+ plasma cells, but not obliterative phlebitis. The mass was surrounded by atrophic thymus. We diagnosed the mass as IgG4-related thymitis. Immunohistochemically, Tregs were scattered throughout the mass. RT-ab-qPCR showed that messenger RNA expressions of TGFB1, IL1B and IFNG in the mass were 270-, 158- and 5.5- fold higher than in the surrounding thymus. His serum IgG4 level after surgery was within the normal range (83.4 mg/dl soon after surgery, 89.3 mg/dl 2 weeks after surgery). CONCLUSIONS: Our results suggested the profibrotic cytokines TGFB1, IL1B and IFNG induce fibrosis and that Tregs might produce some of these cytokines in IgG4-related thymitis as well as in the other affected lesions of IgG4-related disease.

Unsuspected human immunodeficiency virus infection presenting as immunoglobulin G4-related lymphadenopathy: a case report.

Immunoglobulin G4 (IgG4)-related disease (IgG4-RD) is an immune-mediated condition characterized by infiltration of the involved organs by IgG4-bearing plasma cells. The prevalence of autoimmune diseases, associated with or occurring in patients with human immunodeficiency virus (HIV) infection, has been increasing. We describe a 58-year-old man with an undiagnosed HIV infection, which presented as chronic cervical lymphadenopathy with an elevated serum IgG4 and a very high IgE. Histologically, lymph nodes showed expanded sinusoids and burnt-out germinal centers with increased plasmacytic infiltration and collagen fiber deposition. The absolute number of IgG4+ plasma cells and the IgG4+/IgG+ plasma cell ratio was increased. The lymph nodes were enlarged and clinically the patient improved after steroid treatment. Nine months later, he was diagnosed with acquired immune deficiency syndrome, following presentation with a cavitary left lung lesion. Immunohistochemical studies on the previously resected lymph node revealed complete absence of CD4+ T-lymphocytes and increased CD8+ T-lymphocytes. The pathologic findings met the criteria of both HIV infection and IgG4-related lymphadenopathy. Our case demonstrates that further investigations for underlying HIV infection in a case of IgG4-RD are critical, especially when extremely elevated IgE is concomitantly present.

Nodular lymphoid hyperplasia: A marker of low-grade inflammation in irritable bowel syndrome?

AIM: To evaluate the prevalence of nodular lymphoid hyperplasia (NLH) in adult patients undergoing colonoscopy and its association with known diseases. METHODS: We selected all cases showing NLH at colonoscopy in a three-year timeframe, and stratified them into symptomatic patients with irritable bowel syndrome (IBS)-type symptoms or suspected inflammatory bowel disease (IBD), and asymptomatic individuals undergoing endoscopy for colorectal cancer screening. Data collection included medical history and final diagnosis. As controls, we considered all colonoscopies performed for the aforementioned indications during the same period. RESULTS: One thousand and one hundred fifty colonoscopies were selected. NLH was rare in asymptomatic individuals (only 3%), while it was significantly more prevalent in symptomatic cases (32%). Among organic conditions associated with NLH, the most frequent was IBD, followed by infections and diverticular disease. Interestingly, 31% of IBS patients presented diffuse colonic NLH. NLH cases shared some distinctive clinical features among IBS patients: they were younger, more often female, and had a higher frequency of abdominal pain, bloating, diarrhoea, unspecific inflammation, self-reported lactose intolerance and metal contact dermatitis. CONCLUSION: About 1/3 of patients with IBS-type symptoms or suspected IBD presented diffuse colonic NLH, which could be a marker of low-grade inflammation in a conspicuous subset of IBS patients.

[Presence of lactoferrin (LF) in lymphocutaneous sporotrichosis. Yeast-bound antimicrobial peptide]. / Presencia de lactoferrina (LF) en la esporotricosis linfocutánea. Péptido antimicrobiano unido a levaduras.

Sporotrichosis is a common subcutaneous mycosis in Latin America, produced by dimorphic fungi belong to Sporothrix schenckii complex of cryptic species. Infection is acquired by traumatic inoculation with contaminated organic material. Host immune response includes polymorphonuclear neutrophils chemotaxis and release of granular components. Lactoferrin is a protein member of the transferrin family of iron-binding proteins, present inside polymorphonuclear granular structure, and has been reported to affect growth and development of infectious agents, including fungal organisms. Nevertheless, lactoferrin expression in sporotrichosis infections has not been reported yet. OBJECTIVE: To determine the expression of lactoferrin using immunohistochemical staining in sporotrichosis human infection. MATERIAL AND METHODS: The dermatology department's files during a period of five years were reviewed; cases with a diagnosis of sporotrichosis were selected and lactoferrin immunostaining was performed when enough biological material was available. RESULTS: Three cases with a diagnosis of sporotrichosis and adequate biological material on paraffin block were identified. In all cases, lactoferrin immunostaining was positive around yeast cell.

IgG4-related skin disease may have distinct systemic manifestations: a systematic review.

IgG4-related disease (IgG4-RD) is an increasingly prevalent protean multisystem disorder characterized by single or multi-organ infiltration of IgG4-bearing plasma cells. Skin involvement has been recognized and is relevant to proper diagnosis. A systematic literature review of 50 cases involving the skin reveals that patients with IgG4-related skin disease show predominant involvement of the head and neck and have a distinct pattern of systemic involvement, also favoring the head and neck - lymphatics, orbit, salivary, and lacrimal glands - but generally lacking pancreaticobiliary involvement (16% of cases), which by contrast is a predominant manifestation in systemic IgG4-RD (60% with pancreaticobiliary involvement). We summarize clinical and pathologic descriptive data from this systematic review. We review differential diagnosis and propose a diagnostic scheme for stratifying probability of disease based upon comprehensive integration of clinical, histopathologic, and laboratory data. Plasmacyte infiltration and storiform fibrosis are prominent in IgG4-related skin disease, but obliterative venulitis is less common than in the prototypical IgG4-related disease manifestation of autoimmune pancreatitis. IgG4 tissue and serum values, with a mean (±95% CI) in the reviewed cases of 132.8 ± 32.6 IgG4-positive plasma cells per high-power field and 580 ± 183.8 mg/dl, respectively, are incorporated into the suggested criteria. The distinct set of manifestations identified by this systematic review and the proposed diagnostic considerations, while requiring further validation in prospective studies, highlight the need to consider that IgG4-related skin disease defines a unique systemic disease complex along the spectrum of IgG4-RD.

Clinical Associations of Biallelic and Monoallelic TNFRSF13B Variants in Italian Primary Antibody Deficiency Syndromes.

We assessed the prevalence of TNFRSF13B mutations and the clinical correlates in an Italian cohort of 189 CVID, 67 IgAD patients, and 330 healthy controls to substantiate the role of TACI genetic testing in diagnostic workup. We found that 11% of CVID and 13% of IgAD carried at least one mutated TNFRSF13B allele. Seven per cent of CVID had monoallelic-mutations and 4% had biallelic-mutations. The frequency of C104R monoallelic-mutations was not higher than that found in healthy controls. Biallelic-mutations were exclusively found in CVID. CVID patients carrying monoallelic-mutations had an increased prevalence of lymphadenopathy, granulomata, and autoimmune cytopenias. CVID carrying biallelic-mutations had a low prevalence of autoimmunity in comparison with TACI wild-type CVID. Moreover, biallelic-mutated CVID had higher frequency of switched memory B-cells and higher IgM and IgA antibodies to polysaccharide antigens than TACI wild-type and monoallelic-mutated CVID. TACI-mutated IgAD patients had only monoallelic-mutations and did not display clinical difference from IgAD wild-type patients. In conclusion, TNFRSF13B genetic screening of antibody deficiencies may allow the identification of mutational patterns. However, as with counseling for risk assessment, geneticists should be aware that the interpretation of genetic testing for TACI mutations is difficult and the potential impact on clinical management is still limited.

C9orf72 is required for proper macrophage and microglial function in mice.

Expansions of a hexanucleotide repeat (GGGGCC) in the noncoding region of the C9orf72 gene are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. Decreased expression of C9orf72 is seen in expansion carriers, suggesting that loss of function may play a role in disease. We found that two independent mouse lines lacking the C9orf72 ortholog (3110043O21Rik) in all tissues developed normally and aged without motor neuron disease. Instead, C9orf72 null mice developed progressive splenomegaly and lymphadenopathy with accumulation of engorged macrophage-like cells. C9orf72 expression was highest in myeloid cells, and the loss of C9orf72 led to lysosomal accumulation and altered immune responses in macrophages and microglia, with age-related neuroinflammation similar to C9orf72 ALS but not sporadic ALS human patient tissue. Thus, C9orf72 is required for the normal function of myeloid cells, and altered microglial function may contribute to neurodegeneration in C9orf72 expansion carriers.

Autoimmune lymphoproliferative syndrome due to somatic FAS mutation (ALPS-sFAS) combined with a germline caspase-10 (CASP10) variation.

Autoimmune lymphoproliferative syndrome (ALPS) is a primary immunodeficiency caused by impaired Fas/FasL-mediated apoptosis of lymphocytes and is characterized by chronic nonmalignant or benign lymphoproliferation, autoimmune manifestations and expansion of double negative (DN) T-cells (TCRαß+CD4-CD8-). Most cases of ALPS are associated with germline (ALPS-FAS) or somatic (ALPS-sFAS) heterozygous FAS mutations or a combination of both. Here we report three unrelated patients with ALPS-sFAS. Only one of them showed impaired Fas function in PHA-activated T-cells. In this patient, the genetic analysis of the caspase-10 gene (CASP10) identified a heterozygous germline change in exon 9 (c.1337A>G) causing Y446C substitution in the caspase-10 protein. In addition, this patient had a dysregulated T- and B-cell phenotype; circulating lymphocytes showed expansion of T effector memory CD45RA+ (TEMRA) CD4 T-cells, effector memory CD8 T-cells, CD21(low) B-cells and reduced memory switched B-cells. Additionally, this patient showed altered expression in T-cells of several molecules that change during differentiation from naïve to effector cells (CD27, CD95, CD57 and perforin). Molecular alterations in genes of the Fas pathway are necessary for the development of ALPS and this syndrome could be influenced by the concurrent effect of other mutations hitting different genes involved in Fas or related pathways.

Intrathoracic Involvements of Immunoglobulin G4-Related Sclerosing Disease.

To investigate clinical and radiological features of IgG4-related disease (IgG4-RD) patients with intrathoracic involvement. A prospective cohort study was performed and IgG4-RD patients were enrolled from January 2011 to March 2015 in Peking Union Medical College Hospital, in which the clinical and radiological characteristics of IgG4-RD patients with intrathoracic involvement were summarized. Out of total 248 cases with IgG4-RD, 87 cases had intrathoracic lesions, including 58 male cases and 29 female cases, with average age of 54.19 ±â€Š13.80 years. Hilar and mediastinal lymphadenopathy were the most common manifestations of IgG4-related intrathoracic disease, accounting for 52.9% (46/87). Other imaging findings of pulmonary disease included: solid nodular (25.3%), round-shaped ground-glass opacities (9.2%), alveolar-interstitial type (20.7%), bronchovascular type (23.0%), pleural effusion (4.6%), and pleural nodules or thickening (16.1%). Only 27 patients presented with respiratory symptoms, including cough, breathless, chest pain, and asthma. Compared with patients without intrathoracic disease, IgG4-related intrathoracic disease had higher IgG4 and C-reactive protein level, and higher incidence of allergy, fever, and multi-organ involvement. Most of lung interstitial disease, mediastinal mass, and bronchial thickening were sensitive to corticosteroid and immunosuppressant therapy, while 36.3% (8/22) of solitary nodular lesions were unresponsive to treatment. Eight patients were on no treatment, with 5 cases remained stable, 2 patients improved spontaneously, and 1 patient was lost follow-up. Intrathoracic lesions are not rare in patients with IgG4-RD, involving bronchial thickening, nodules, ground glass opacity, pleural thickening/effusion, lymphadenopathy, etc. Efficacy of corticosteroid and immunosuppressant therapy were noted in most of patients with lung interstitial disease, mediastinal mass, and bronchial thickening.

Lymphocytosis, lymphadenopathy: benign or malignant?

The increasing use of immunophenotypic and molecular analysis in the routine evaluation of patients with lymphocytosis, lymphadenopathy, or other hematologic disorders has led to the identification of unexpected small clonal lymphoid populations. These clones, sometimes with disease-specific markers, such as the t(14;18), are especially challenging for the clinician because of their unknown biologic potential and uncertain clinical behavior. Study of these early lymphoid lesions is providing important clues to the process of lymphomagenesis, and may provide the rationale for preemptive therapy in the future. More and more, the hematologist/oncologist is consulted regarding otherwise healthy individuals with lymphadenopathy and/or lymphocytosis, and pathology reports that confound the referring internist or surgeon. The report does not name a malignant lymphoproliferative disorder, but is not completely "normal". Does the patient have a benign or malignant condition? How should they be evaluated? Is treatment indicated? These patients prove challenging for the consulting hematologist as well as the referring physician. In this review, we will focus on some of these scenarios and attempt to provide guidance for their management.

IgG4-related prostatitis progressed from localized IgG4-related lymphadenopathy.

Immunoglobulin G4-related disease (IgG4-RD) is a recently described inflammatory disease involving multiple organs. Prostate involvement with IgG4-RD is very rare. In this report, we describe a case of IgG4-related prostatitis progressed from localized IgG4-related lymphadenopathy. This patient was present with urine retention symptoms. MRI and CT examination revealed the prostatic enlargement and the multiple lymphadenopathy. Serum IgG4 levels were elevated. Prostatic tissue samples resected both this time and less than 1 year earlier showed the same histological type of prostatitis with histopathologic and immunohistochemical findings characteristic of IgG4-RD. The right submandibular lymph nodes excised 2 years earlier were eventually proven to be follicular hyperplasia-type IgG4-related lymphadenopathy. This is the first case of IgG4-RD that began as localized IgG4-related lymphadenopathy and progressed into a systemic disease involving prostate and multiple lymph nodes. This patient showed a good response to steroid therapy. This leads us to advocate a novel pathogenesis of prostatitis, and a novel therapeutic approach against prostatitis. Pathologists and urologists should consider this disease entity in the patients with elevated serum IgG4 levels and the symptoms of prostatic hyperplasia to avoid ineffective medical or unnecessary surgical treatment.

Hairy cell leukemia: Uncommon clinical features, unusual sites of involvement and some rare associations.

Unusual clinical manifestations and associations with auto-immunity or other systemic disorders are uncommon clinical features of hairy cell leukemia (HCL). The exact prevalence of these rare associations is difficult to determine as they are mostly published as anecdotal case reports and generally not included in larger published series. This chapter deals with uncommon clinical manifestations and rare sites of involvement in HCL. It also summarizes the association with systemic hemato-oncological disorders as well as second malignancies, based on review of the relevant literature and from personal experience.

Revisiting the Mechanisms of CNS Immune Privilege.

Whereas the study of the interactions between the immune system and the central nervous system (CNS) has often focused on pathological conditions, the importance of neuroimmune communication in CNS homeostasis and function has become clear over that last two decades. Here we discuss the progression of our understanding of the interaction between the peripheral immune system and the CNS. We examine the notion of immune privilege of the CNS in light of both earlier findings and recent studies revealing a functional meningeal lymphatic system that drains cerebrospinal fluid (CSF) to the deep cervical lymph nodes, and consider the implications of a revised perspective on the immune privilege of the CNS on the etiology and pathology of different neurological disorders.