Genetic Associations and Differential mRNA Expression Levels of Host Genes Suggest a Viral Trigger for Endemic Pemphigus Foliaceus.

The long search for the environmental trigger of the endemic pemphigus foliaceus (EPF, fogo selvagem) has not yet resulted in any tangible findings. Here, we searched for genetic associations and the differential expression of host genes involved in early viral infections and innate antiviral defense. Genetic variants could alter the structure, expression sites, or levels of the gene products, impacting their functions. By analyzing 3063 variants of 166 candidate genes in 227 EPF patients and 194 controls, we found 12 variants within 11 genes associated with differential susceptibility (p < 0.005) to EPF. The products of genes TRIM5, TPCN2, EIF4E, EIF4E3, NUP37, NUP50, NUP88, TPR, USP15, IRF8, and JAK1 are involved in different mechanisms of viral control, for example, the regulation of viral entry into the host cell or recognition of viral nucleic acids and proteins. Only two of nine variants were also associated in an independent German cohort of sporadic PF (75 patients, 150 controls), aligning with our hypothesis that antiviral host genes play a major role in EPF due to a specific virus−human interaction in the endemic region. Moreover, CCL5, P4HB, and APOBEC3G mRNA levels were increased (p < 0.001) in CD4+ T lymphocytes of EPF patients. Because there is limited or no evidence that these genes are involved in autoimmunity, their crucial role in antiviral responses and the associations that we observed support the hypothesis of a viral trigger for EPF, presumably a still unnoticed flavivirus. This work opens new frontiers in searching for the trigger of EPF, with the potential to advance translational research that aims for disease prevention and treatment.

Clinical Diagnosis of Herpes Simplex-Infected Pemphigus Erosions.

Clinical diagnosis of Herpes simplex-infected pemphigus erosions is challenging. Pemphigus and Herpes simplex both produce superficial erosions on the skin and mucosa after rupture of vesicles or bullae. Delay in diagnosis of herpes-infected pemphigus patients often causes prolonged morbidity. So far, there has been a paucity of literature describing the characteristic features of Herpes simplex-infected pemphigus erosions. In the present case series, we have illustrated the morphologic features of three Herpes simplex-infected pemphigus erosions and also have suggested characteristic clinical features that were consistently present in all cases.

Refractory pemphigus foliaceus associated with herpesvirus infection: case report.

Pemphigus foliaceus (PF) is an autoimmune disease characterized by blistering of the skin. Infections caused by members of the herpesviridae family have been suggested as a possible triggering factor for pemphigus vulgaris (PV), but not for PF. The present study aimed to investigate the presence of Human herpesvirus (types 1, 2, 3) in corticosteroid refractory skin lesions from a patient with PF, by a Polymerase chain reaction (PCR) assay. The sample collected from cutaneous blisters has tested positive for herpes simplex virus type 1 (HSV1) after sequence analysis of the amplified viral genomic segment. The study concluded that when PF patients present corticosteroid or immunosuppressants refractory lesions, herpetic infection should be considered.

Herpes simplex virus 1 and cytomegalovirus are associated with pemphigus vulgaris but not with pemphigus foliaceus disease.

Pemphigus vulgaris (PV) and pemphigus foliaceus (PF) are blistering autoimmune diseases that depend on interaction between genetic and environmental factors. Viral infections, like herpes simplex viruses 1 and 2 (HSV1/2), cytomegalovirus (CMV), Epstein-Barr virus and dengue virus, could trigger or exacerbate pemphigus. IgM and IgG antibodies against these viruses in serum from PV and PF, their relatives and controls were determined. HSV1/2 expression was evaluated by direct immunofluorescence (DIF) and qPCR in affected or not oral mucosa from PV patients compared with uninjured PF mucosa. IgG anti-HSV1 was higher in the PV group compared with all groups. IgG anti-CMV resulted higher in PV group compared with PF patients and PV relatives. HSV1 was confirmed by DIF and qPCR on oral samples from patients with PV. Lack of HSV1 expression in the oral mucosa of patients with PF corroborate that immunosuppressive therapy cannot be the main cause for HSV1 replication in PV disease.

Positive correlation of anti-herpes simplex type I virus antibody levels with pemphigus vulgaris disease status and activity in a large patient cohort.

It is well accepted that pemphigus vulgaris (PV) is genetically linked to specific HLA class II subtypes. Environmental factors, including the role of herpes simplex virus (HSV1) in disease manifestation, have also been implicated, but in a limited number of patients and with inconsistent results. To clarify an association between HSV1 and PV in a large data set, including a stratification by dynamic and static clinical parameters, including disease activity, therapy status, HLA association, and gender. Serum HSV1 IgG levels from PV patients and healthy controls were measured by ELISA. Subjects were typed for HLA class II DRB1 and DQB1 alleles, and categorized as HLA-matched if homozygous or heterozygous for either one of the known PV-susceptibility alleles, DRB1*0402 and DQB1*0503. Our data indicate that PV patients carry significantly higher levels of anti-HSV1 antibodies than healthy controls, and that this effect was more pronounced in the active phase of disease when compared to remission. A mild positive association could also be observed for carriers of the PV-associated HLA alleles versus HLA-unmatched controls, as well as for female PV patients when compared to female control subjects. Our data suggest a role of HSV1 in the expression of PV and further show that HLA status and gender may influence HSV1 susceptibility and/or expression of anti-HSV1 antibodies. Additional research with larger datasets is required to determine whether HSV is causally linked to PV pathogenesis and conclusively link HLA status and gender to HSV1 antibody levels.

Viruses and pemphigus: an intriguing never-ending story.

Virus infections and autoimmunity have long been linked. As to pemphigus, many studies have been directed to prove or rule out the possibility of viral induction. Herpesviruses have often been related to the onset or reactivation of pemphigus. The association may be (i) casual, (ii) due to the iatrogenic immunosuppression facilitating opportunistic viral infections or (iii) based on a pathogenic link between the viral presence and the host's dysregulated immune response leading to autoimmunity. Japanese researchers, using real-time polymerase chain reaction, lately detected herpes simplex virus DNA in the saliva from pemphigus patients at the earliest stage of the disease and with no signs or history of herpetic infection, thus confirming the possible existence of cases of pemphigus induced by herpesviruses. These selected cases could be included into the innovative concept of 'paraviral eruptions', where an inciting role for induction may be played by the concomitant intake of certain drugs.

Hepatitis C and hepatitis B virus infections in the etiopathogenesis of pemphigus.

BACKGROUND: Previous studies have shown that some viral infections may be triggers for autoimmune diseases. The role of viral infections in the etiopathogenesis of pemphigus has also been investigated. OBJECTIVES: To investigate the relationship between pemphigus and the hepatitis B and C virus infections. METHODS: This retrospective study included 62 patients with pemphigus and 50 healthy controls of matching ages and genders. The control group included relatives who accompanied the orthopedic patients to the hospital but had no history of systemic and/or autoimmune diseases. RESULTS: The group of patients with pemphigus was composed of 43 (69.3%) females and 19 (29.7%) males, and the mean age was 48.08 ± 15.38. The hepatitis C virus antibody was negative in all of the patients. Hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (HBsAb), or both, were studied in 44 of the 62 patients. Two (4.3%) of these patients were positive for HBsAg and found to have HBV infection. Fourteen of them were HBsAb positive. Two (4%) of the 50 control subjects showed hepatitis C virus antibody positivity, while only 1 (2%) patient with pemphigus displayed HBsAg positivity. There was no statistically significant difference between the two groups for hepatitis B and C virus infections. CONCLUSIONS: This study does not support an association between pemphigus and hepatitis B and/or C virus infections.

Hepatitis C and hepatitis B virus infections in the etiopathogenesis of pemphigus

BACKGROUND: Previous studies have shown that some viral infections may be triggers for autoimmune diseases. The role of viral infections in the etiopathogenesis of pemphigus has also been investigated. OBJECTIVES: To investigate the relationship between pemphigus and the hepatitis B and C virus infections. METHODS: This retrospective study included 62 patients with pemphigus and 50 healthy controls of matching ages and genders. The control group included relatives who accompanied the orthopedic patients to the hospital but had no history of systemic and/or autoimmune diseases. RESULTS: The group of patients with pemphigus was composed of 43 (69.3%) females and 19 (29.7%) males, and the mean age was 48.08 ± 15.38. The hepatitis C virus antibody was negative in all of the patients. Hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (HBsAb), or both, were studied in 44 of the 62 patients. Two (4.3%) of these patients were positive for HBsAg and found to have HBV infection. Fourteen of them were HBsAb positive. Two (4%) of the 50 control subjects showed hepatitis C virus antibody positivity, while only 1 (2%) patient with pemphigus displayed HBsAg positivity. There was no statistically significant difference between the two groups for hepatitis B and C virus infections. CONCLUSIONS: This study does not support an association between pemphigus and hepatitis B and/or C virus infections. .

Herpes simplex virus reactivation as a trigger of mucous lesions in pemphigus vulgaris.

BACKGROUND: Although infectious agents have long been implicated in the induction or exacerbation of pemphigus vulgaris (PV), a convincing role for the agent in the aetiology of PV has not been established. OBJECTIVES: To establish the association with PV and herpes simplex virus (HSV). PATIENTS AND METHODS: We examined saliva for the presence of HSV DNA after the onset of PV initially localized to the oral lesions in addition to conventional serological tests and immunohistochemistry. RESULTS: We successfully detected high levels of HSV DNA in the saliva samples from six of 16 patients with PV at the earliest stage, who had no episodes of herpes simplex. The prevalence (37·5%) of detecting HSV DNA in the patients with PV was lower than that of eczema herpeticum (56·5%), but comparable to that in patients with herpes labialis (30·0%). Copy numbers of the HSV DNA were rather higher than those with herpes labialis and with eczema herpeticum. In general, detection of HSV DNA in saliva was transient and restricted to the earliest phase of the disease. In addition, anti-HSV immunoglobulin (Ig) G titres in patients with PV were significantly higher than those in patients with virologically confirmed HSV-induced disorders. All salivary HSV DNA-positive patients with PV had run a more complex, intractable course refractory to conventional therapy. CONCLUSIONS: Detection of HSV DNA in saliva is a useful and noninvasive, quantitative method for establishing the role of HSV in the pathogenesis of PV and for identifying individuals at greater risk for subsequently developing refractory PV.

Pemphigus vulgaris in a patient with arthritis and uveitis: successful treatment with immunosuppressive therapy and acyclovir.

A case of pemphigus vulgaris in a 41-year-old man with undifferentiated arthritis and uveitis is described. Histology of labial mucosa showed acantholytic, necrotic, and multinucleated giant keratinocytes having some nuclear inclusions suggestive of a virus infection. Specific serological tests revealed IgG positivity for HSV-1, CMV, and EBV, while real-time polymerase chain reaction assay from a biopsy of the mucosal lesion showed the presence of HSV-1/2 DNA. Treatment with prednisone, methotrexate, and acyclovir induced the complete remission of mucosal and joint symptoms, which then relapsed after interruption of antiviral therapy or immunosuppressive therapy. Therefore, a combined treatment with low doses of prednisone, methotrexate, and acyclovir was restarted and during 18 months of follow-up no recurrence was registered. Correlations between pemphigus and the herpes virus infection and also between autoimmune arthritis and herpetic agents have been well documented, but the exact role of the herpes virus in these disorders still needs further discussion. Our case strongly suggests that when autoimmune disorders do not respond to immunosuppressive agents, a viral infection should be suspected, researched, and treated.

The investigation of the possible relationship between Coxsackie viruses and pemphigus.

BACKGROUND: Pemphigus is a group of autoimmune bullous diseases on which the etiopathogenesis of several viruses has been blamed. Coxsackie viruses (CVs) are the causative agents of hand, foot, and mouth disease, and herpangina, which have been strongly associated with several autoimmune diseases. The onset of pemphigus after CV infection and cephalosporin use has been reported. OBJECTIVE: To detect the presence of CV in patients with pemphigus. MATERIALS AND METHODS: Reverse transcriptase-polymerase chain reaction analysis for CV RNA sequences and immunohistochemical staining for the CV and adenovirus receptor expression were performed on patient skin samples. CV-IgM and -IgG serum levels were analyzed. RESULTS: Thirty-two patients and 40 controls were investigated. Neither the CV and adenovirus receptor expression nor CV RNA sequences was established in the skin samples of patients. The ratio of CV-IgG positivity was higher in patients (12.5%) than in the controls (5%; P > 0.05). CONCLUSION: Our preliminary results indicate that the viral genome of CV does not become persistent in the skin. Further studies with a larger number of cases are needed to clarify the place of CVs in the etiopathogenesis of pemphigus.

Laboratory diagnosis of herpesvirus infections in patients with Pemphigus vulgaris lesions.

BACKGROUND/AIMS: Pemphigus vulgaris (PV) is an autoimmune disorder that has an etiology impacted by genetic and exogenous factors. Viral infections, in particular herpesvirus infections, have been identified as possible PV triggers which in addition cause serious complications in these patients. This study investigates the frequency of herpesvirus infections in patients with PV lesions. METHODS: Polymerase chain reaction and DNA sequence analyses were used to determine the presence of herpes simplex virus (HSV)-1/2, varicella-zoster virus (VZV), Epstein-Barr virus (EBV), cytomegalovirus (CMV), and human herpesvirus types 6, 7, and 8 (HHV-6, HHV-7, and HHV-8) DNA in 105 mucosal and/or skin swabs harvested from 23 patients presenting with PV lesions. RESULTS: Thirty-six samples collected from 17 patients were positive for at least 1 virus; 3 were positive for HSV-1, 2 for HSV-2, 2 for CMV, and 7 each for HHV-6 and HHV-7. Coinfections were observed in 15 samples. Infections with VZV, EBV, HHV-6A, and HHV-8 were not detected. Herpesvirus infections were detected in 21% (13/62) of reactivated lesions, 54.5% (18/33) in persistent lesions, 40% (2/5) in exacerbated lesions, and 60% (3/5) in lesions in remission. CONCLUSION: PV lesions which do not show improvement following administration of adequate immunosuppressive therapy should be screened for the presence of herpesvirus infections.

Exploring the link between herpes viruses and pemphigus vulgaris: literature review and commentary.

Pemphigus vulgaris (PV) is an autoimmune skin condition characterized by the presence of circulating autoantibodies specific for a subset of cellular adhesion proteins within mucosal and/or non-mucosal epidermal surfaces. Although the presence of self-directed antibodies is well established, the exact etiology of PV is still uncertain. Environmental factors have been linked to a variety of autoimmune disorders. Specifically, viral infection has been considered to act as one contributory component in disease pathogenesis. Perhaps the most studied group of pathogens is that of herpes viruses, with considerable evidence linking the herpes simplex virus and PV. These viruses have been reported to influence the course of disease and have been associated with PV flares and clinical exacerbations. However, there are significant inconsistencies amongst published data; additional analysis is required to solidify the proposed relationship. In the following article, we critically review the literature regarding the impact of the herpes viruses on PV, providing a framework for clinical application, mechanistic pathways, and future investigation.

Paraneoplastic pemphigus and Castleman's disease in the setting of herpes simplex virus infection.

A 14-year-old girl presented with a 3-week history of mucosal erosions, injected conjunctiva, dehydration, and respiratory distress. She had been treated with intravenous acyclovir for herpes simplex infection with positive herpes simplex virus immunoglobulin M and immunoglobulin G. Physical examination and imaging revealed a large abdominal mass. Incisional biopsy was obtained, and pathology demonstrated angiofollicular hyperplasia with hyalinized germinal centers and Castleman's syndrome-like features. Based on the mucosal erosions, herpes simplex virus serology and positive herpes simplex virus-1 direct fluorescent antibody, Castleman's disease secondary to overwhelming herpes simplex virus infection was the initial impression. The poor response to antivirals and subsequent development of a bullous eruption on the hands resulted in dermatology consultation. Skin biopsy was obtained from a bullae and revealed suprabasilar acantholysis with necrosis as well as upper dermal, perivascular, and interface infiltrate of lymphocytes and eosinophils. No viropathic changes were present. Direct immunofluorescence was significant for immunoglobulin G deposition intercellularly and along the dermoepidermal junction and focal trace C3 deposition along the dermoepidermal junction consistent with paraneoplastic pemphigus, later confirmed by indirect immunofluorescence. We report this case of paraneoplastic pemphigus secondary to Castleman's syndrome confounded by herpes simplex virus-1 positive mucosal erosions.

Herpes simplex virus-induced plasmacytic atypia.

The clinical and histopathological features of cutaneous herpes simplex virus (HSV) infection have been well described. Genital herpetic infections are largely induced by HSV type 2, but 30% of cases can be caused by HSV type 1. Immunocompromised patients are known to exhibit atypical patterns of clinical presentation with variable lesion morphology and anatomic location. A subset of patients may show morphology such as nodules or verrucous lesions. Analogously, some biopsy specimens may show unusual microscopical features, such as a lack of keratinocyte cytopathology, lymphocyte infiltration or vasculopathic changes that are expected irrespective of the patient's immune status. We present the case of a patient carrying a previous diagnosis of pemphigus vulgaris, status posttreatment with methotrexate and prednisone, who developed a perineal ulcer exhibiting significant numbers of plasma cells, many of which were cytologically atypical. This morphology was suggestive of a hematopoietic malignancy. Immunoperoxidase staining for HSV decorated a focal collection of keratinocytes that lacked appreciable viral changes expected of HSV infection.

Pemphigus vulgaris and herpesviruses: is there any relationship?

BACKGROUND: Pemphigus is an autoimmune disorder, which results from interaction of exogenous and endogenous factors. One of these environmental factors is viral infections particularly, herpesviruses. We aimed to detect the presence of HSV 1 and 2 (herpes simplex virus) and HHV8 (human herpesvirus 8) in our patients who were suffering from pemphigus vulgaris. METHODS: In this cross-sectional study, 38 patients (19 male and 19 female patients) with pemphigus vulgaris were entered, 32 skins and six peripheral blood cells samples were obtained from the study population. Thereafter, the presence of HHV8 and HSV DNA were evaluated by using polymerase chain reaction (PCR). RESULTS: The mean age of patients was 45.05 ± 17.24 years (range: 16-81 years). Twelve patients mentioned history of herpes labial in the past (31.57%). Results of PCR test for detection of HSV and HHV8 DNA in all 32 skin samples and five peripheral blood samples and one case with skin and blood samples were reported negative. CONCLUSION: Inability to detect HHV8 and HSV DNA in this study suggests that herpesviruses may be only occasional factors for development or exacerbation of pemphigus vulgaris.

Evaluation of coexistence of the Human Herpesvirus type 8 (HHV-8) infection and pemphigus.

BACKGROUND: Human Herpesvirus type 8 (HHV-8) is a new member of the herpes virus family, first found in the tissue of acquired immune deficiency syndrome (AIDS)-related Kaposi's sarcoma. Environmental factors including viral infection may play a role in the onset and/or development of pemphigus. Some studies based on polymerase chain reaction findings suggest an association between HHV-8 and pemphigus. The aim of this study is investigation of the association of pemphigus with HHV-8 and the relationship between inflammatory and acantholytic cells with HHV-8 infection. METHODS: Tissue-extracted DNA from 41 paraffin-embedded skin tissues from patients first presenting with pemphigus was tested using nested PCR for the presence of HHV-8. A total of 37 cases had pemphigus vulgaris (PV) and 4 patients had pemphigus foliaceus (PF). For our control group, normal skin of 21 cosmetic surgery patients were included. Furthermore, microscopic slides with H&E staining were evaluated for the number of inflammatory and acantholytic cells per microscopic field. RESULTS: Skin lesions from 13 of 37 patients (35.1%) with PV and 2 of 4 cases (50%) with PF were positive for HHV-8 DNA. All specimens in our control group were negative for this virus. CONCLUSION: HHV-8 infection might be a contributing factor in the initiation or development of pemphigus.