Acute neutrophilic vasculitis (leukocytoclasia) in 36 COVID-19 autopsy brains.

BACKGROUND: Hypercytokinemia, the renin-angiotensin system, hypoxia, immune dysregulation, and vasculopathy with evidence of immune-related damage are implicated in brain morbidity in COVID-19 along with a wide variety of genomic and environmental influences. There is relatively little evidence of direct SARS-CoV-2 brain infection in COVID-19 patients. METHODS: Brain histopathology of 36 consecutive autopsies of patients who were RT-PCR positive for SARS-CoV-2 was studied along with findings from contemporary and pre-pandemic historical control groups. Immunostaining for serum and blood cell proteins and for complement components was employed. Microcirculatory wall complement deposition in the COVID-19 cohort was compared to historical control cases. Comparisons also included other relevant clinicopathological and microcirculatory findings in the COVID-19 cohort and control groups. RESULTS: The COVID-19 cohort and both the contemporary and historical control groups had the same rate of hypertension, diabetes mellitus, and obesity. The COVID-19 cohort had varying amounts of acute neutrophilic vasculitis with leukocytoclasia in the microcirculation of the brain in all cases. Prominent vascular neutrophilic transmural migration was found in several cases and 25 cases had acute perivasculitis. Paravascular microhemorrhages and petechial hemorrhages (small brain parenchymal hemorrhages) had a slight tendency to be more numerous in cohort cases that displayed less acute neutrophilic vasculitis. Tissue burden of acute neutrophilic vasculitis with leukocytoclasia was the same in control cases as a group, while it was significantly higher in COVID-19 cases. Both the tissue burden of acute neutrophilic vasculitis and the activation of complement components, including membrane attack complex, were significantly higher in microcirculatory channels in COVID-19 cohort brains than in historical controls. CONCLUSIONS: Acute neutrophilic vasculitis with leukocytoclasia, acute perivasculitis, and associated paravascular blood extravasation into brain parenchyma constitute the first phase of an immune-related, acute small-vessel inflammatory condition often termed type 3 hypersensitivity vasculitis or leukocytoclastic vasculitis. There is a higher tissue burden of acute neutrophilic vasculitis and an increased level of activated complement components in microcirculatory walls in COVID-19 cases than in pre-pandemic control cases. These findings are consistent with a more extensive small-vessel immune-related vasculitis in COVID-19 cases than in control cases. The pathway(s) and mechanism for these findings are speculative.

The Anti-inflammatory Effects of HMGB1 Blockades in a Mouse Model of Cutaneous Vasculitis.

In our previous study, we have found increased serum levels of HMGB1 in patients with Henoch- Schonlein purpura (HSP), allergic vasculitis (AV), and urticarial vasculitis (UV) and altered HMGB1 distribution in lesional skin in patients with HSP. HMGB1 plays a pro-inflammatory role in the pathogenesis of HSP. To further investigate the role of HMGB1 in the pathogenic mechanism of vasculitis, we investigated the anti-inflammatory effects of HMGB1 blockades (including anti-HMGB1 mAb and glycyrrhizin) in a mouse model of a cutaneous reverse passive Arthus (RPA) reaction. A total of 36 balb/c mice were randomly divided into four groups: the control group, IC model group, HMGB1 monoclonal antibody (anti-HMGB1-mAb) group and the glycyrrhizin group, with nine mice in each group. A cutaneous RPA reaction mouse model was established by injections of the OVA antibody and the OVA antigen. Mice of the anti-HMGB1-mAb group and glycyrrhizin group were pre-treated with anti-HMGB1 mAb or glycyrrhizin, respectively, before the RPA reaction. Our results indicated that HMGB1 blockades (anti-HMGB1 mAb and glycyrrhizin) obviously extenuated the severity of vasculitis skin damage and improved the histological evolvement of inflammatory cells infiltration, vascular fibroid necrosis, and vasodilation in a cutaneous RPA reaction mouse model. In addition, HMGB1 blockades reduced the infiltration of neutrophils, DCs, and T cells and decreased the mRNA expression of IL-6 and CCL5 in skin lesions in the cutaneous RPA reaction mouse model. We suggest that HMGB1 blockades may represent a new direction for the treatment of cutaneous vasculitis.

Expanding the Organismal Proteostasis Network: Linking Systemic Stress Signaling with the Innate Immune Response.

Stress response pathways regulate proteostasis and mitigate macromolecular damage to promote long-term cellular health. Intercellular signaling is an essential layer of systemic proteostasis in an organism and is facilitated via transcellular signaling molecules that orchestrate the activation of stress responses across tissues and organs. Accumulating evidence indicates that components of the immune response act as signaling factors that regulate the cell-non-autonomous proteostasis network. Here, we review emergent advances in our understanding of cell-non-autonomous regulators of proteostasis networks in multicellular settings, from the model organism, Caenorhabditis elegans, to humans. We further discuss how innate immune responses can be players of the organismal proteostasis network and discuss how both are linked in cancer.

Histopathology of bilateral lower extremity inflammatory lymphedema in military basic trainees: A leukocytoclastic vasculitis of the deep vascular plexus.

Bilateral lower extremity inflammatory lymphedema (BLEIL) is a recently described condition that presents with exquisite tenderness, erythema and edema of the lower leg, ankle and dorsal foot resembling an acute cellulitis. It was first reported in healthy, young adult military basic trainees with a normal body mass index during the first 72 hours of arrival to basic training. It occurs while standing at attention for many hours, and shows rapid resolution with elevation and rest. We report an additional case of BLEIL and describe the histopathology of this case and 2 of the previously reported cases. All 3 biopsies showed a deep perivascular infiltrate of neutrophils with karyorrhectic debris and prominent red blood cell extravasation. One of the 3 cases was positive for complement by direct immunofluorescence. We postulate this condition represents a deep leukocytoclastic vascultis with secondary reactive lymphedematous changes.

Annular lesions of cutaneous sarcoidosis with granulomatous vasculitis.

Sarcoidosis is known to be involved in diseases with vasculitis as sarcoid vasculitis. However, vasculitis in cutaneous sarcoidal lesions is extremely rare. Here we describe a case of sarcoidosis with multiple annular skin lesions with granulomatous vasculitis. A 62-year-old female was diagnosed with sarcoidosis by chest-abdominal computed tomographic examination and laboratory tests. The skin lesions had appeared on her lower limbs 2 years before. Physical examination showed multiple infiltrated annular eruptions on the lower extremities. A skin biopsy of an area of erythema showed multiple non-caseating epithelioid cell granulomas in the dermis and subcutaneous fat and granulomatous vasculitis with fibrinoid degeneration in the subcutaneous fat. There are two types of vasculitis in sarcoidosis: leukocytoclastic and granulomatous vasculitis. Ulcers and livedo were more common in granulomatous vasculitis than in leukocytoclastic vasculitis. The present case had unique annular skin lesions of sarcoidosis with granulomatous vasculitis.

Leukocytoclastic vasculitis in children: clinical characteristics, subtypes, causes and direct immunofluorescence findings of 56 biopsy-confirmed cases.

BACKGROUND: Leukocytoclastic vasculitis (LCV) in children is a complex group of conditions. OBJECTIVES: This study presents the demographics, clinical features, direct immunofluorescence (DIF) results and suspected aetiologies of 56 biopsy-confirmed cases of leukocytoclastic vasculitis in children. METHODS: Retrospective review of 56 children seen at Mayo Clinic in Rochester, Minnesota, from 1993 to 2013 with clinical features and cutaneous biopsy consistent with LCV. RESULTS: Twenty-seven (48%) cases were found to be due to IgA vasculitis (Henoch-Schonlein purpura). The remaining cases were found to be due to cutaneous small-vessel vasculitis (n = 19, 34%), urticarial vasculitis (n = 5, 9%), ANCA-associated vasculitis (n = 4, 7%) and acute haemorrhagic oedema of infancy (n = 1, 2%). IgA vasculitis was found to be associated with abdominal pain (P = 0.008), whereas the non-IgA vasculitis group was associated with headache (P = 0.052). Children with IgA vasculitis had palpable purpura (P = <0.001), petechia (P = 0.057), vesicles (P = 0.009) and involvement of the buttock (P = 0.004) more frequently than the non-IgA vasculitis group. On DIF, perivascular IgA was positive in IgA vasculitis compared to non-IgA vasculitis cases (P = <0.001), the other conjugates were similar between the two groups. CONCLUSION: The most common subtype of biopsy-confirmed LCV in children is IgA vasculitis. Clinical features, exam characteristics and DIF results can be helpful in determining the subtype of cutaneous vasculitis in children.

TWEAK enhances E-selectin and ICAM-1 expression, and may contribute to the development of cutaneous vasculitis.

Our previous work indicated that TWEAK is associated with various types of cutaneous vasculitis (CV). Herein, we investigate the effects of TWEAK on vascular injury and adhesion molecule expression in CV mice. We showed that TWEAK priming in mice induced a local CV. Furthermore, TWEAK priming also increased the extravasation of FITC-BSA, myeloperoxidase activity and the expression of E-selectin and ICAM-1. Conversely, TWEAK blockade ameliorated the LPS-induced vascular damage, leukocyte infiltrates and adhesion molecules expression in LPS-induced CV. In addition, TWEAK treatment of HDMECs up-regulated E-selectin and ICAM-1 expression at both mRNA and protein levels. TWEAK also enhanced the adhesion of PMNs to HDMECs. Finally, western blot data revealed that TWEAK can induce phosphorylation of p38, JNK and ERK in HDMECs. These data suggest that TWEAK acted as an inducer of E-selectin and ICAM-1 expression in CV mice and HDMECs, may contribute to the development of CV.

Granuloma faciale: a cutaneous lesion sharing features with IgG4-associated sclerosing diseases.

The pathogenesis of granuloma faciale (GF), framed in the group of cutaneous vasculopathic dermatitis, is poorly understood. The present study investigated whether GF might be part of the spectrum of IgG4-related sclerosing diseases (IgG4-RD). Erythema elevatum diutinum (EED), believed to belong to the same group of disorders as GF, was also studied for comparison. Thirty-one biopsies of GF obtained from 25 patients (18 men, 7 women) and 5 cases of EED (4 women and 1 man) were analyzed morphologically and for the expression of IgG and IgG4 by immunohistochemistry. The distribution of Th1, T regulatory and Th2 T-cell subsets, respectively, identified by anti-T-bet, anti-FoxP3, and anti-GATA-3 antibodies, was also evaluated. The dermal inflammatory infiltrate in GF contained eosinophils and plasma cells in variable proportions. Obliterative venulitis was found in 16 cases, and storiform fibrosis, a typical feature of IgG4-RD, was observed in 8 cases and was prominent in 3 of them. On immunohistochemical analysis 7 of 31 biopsies (22.6%) from 6 GF patients fulfilled the criteria for IgG4-RD (IgG4/IgG ratio >40%, and absolute number of IgG4 per high-power field >50). Interestingly, the 6 patients were male, and 4 showed recurrent and/or multiple lesions. In an additional 5 cases, only the IgG4/IgG ratio was abnormal. None of the 5 EED cases fulfilled the criteria for IgG4-RD. The T-cell subsets in GF were quite variable in number, GATA-3 lymphocytes were generally more abundant, but no relationship with the number of IgG4 plasma cells was found. The study indicates that a significant number of GF cases are associated with an abnormal content of IgG4 plasma cells; this association was particularly obvious in male patients and in cases presenting with multiple or recurrent lesions. As morphologic changes typically found in IgG4-RD, such as obliterative vascular inflammation and storiform sclerosis, are found in GF, we suggest that GF might represent a localized form of IgG4-RD.

Myelodysplasia and malignancy-associated vasculitis.

While the link between malignancy and vasculitis has been known for some time, the association of vasculitis and myelodysplastic syndrome (MDS) has only recently been reported. This article reviews the most current and landmark publications regarding MDS, as well as malignancy-associated vasculitis. We include theories of paraneoplastic associations, immune pathogenesis including an associated cytokine transcriptional factor (interferon regulatory factor-1 [IFN-1]), and the relationship to treatment. Key clinical features that suggest underlying malignancy in patients with vasculitis are highlighted. Although the association between vasculitis and malignancy is rare, leukocytoclastic vasculitis is the most common vasculitis associated with MDS, hematologic malignancies as well as solid tumors. We review several articles that demonstrate a paraneoplastic association between vasculitis and various malignancies, but overall, the connection is still unclear and not well defined. Certain features that suggest a true paraneoplastic association are outlined. Further studies are needed to advance our understanding of this complex topic.

Acute febrile neutrophilic dermatosis: a histopathologic study of 31 cases with review of literature.

Sweet syndrome is a neutrophilic dermatosis defined by diagnostic criteria that include the lack of evidence for leukocytoclastic vasculitis. Because of the clinicopathological similarities on the one hand and the strict exclusion on the other hand, we were interested in a systematic evaluation of the relationship between these two diseases. We investigated the clinical and histopathological characteristics of 31 patients with Sweet syndrome, comparing our cases with 32 cases of leukocytoclastic vasculitis (including seven cases of urticarial vasculitis) and tried to place them in the background of published cases. There is a close relationship between Sweet syndrome and leukocytoclastic vasculitis in terms of clinical appearance, histopathological pattern, triggers, disease course, and response to treatment. The majority of the cases (23/31; 74%) showed histologic evidence of vasculitis, including nuclear dust, extravasation of erythrocytes, fibrin in and around vessel walls, and degeneration of collagen. Although one original criterion for Sweet syndrome is the absence of vasculitis, we propose that vasculitic changes should not exclude the diagnosis of Sweet syndrome. In contrast, Sweet syndrome can demonstrate vasculitis and may, similarly to urticarial vasculitis, be regarded a variant of leukocytoclastic vasculitis. Clinicopathologic characteristics with acute onset of juicy papules, plaques mostly on the face, shoulder, and trunk, and prominent edema probably reflect modifications of the pathogenetic process based on location and disease acuity.

Urticarial vasculitis.

A case of urticarial vasculitis (UV) is presented. The pathogenesis, clinical characteristics, diagnosis, and management of this disease are reviewed, followed by clinical pearls and pitfalls for the practicing allergist (Venzor J, et al., Urticarial vasculitis, Clin Rev Allergy Immunol 23:201-216, 2002). The lesions in UV typically lasts > 24 hours in a fixed location, resolves with residual hyperpigmentation, and may or may not be pruritic. In contrast, standard urticaria lesions persist < 24 hours, leave no trace, and is always pruritic (Black AK, Urticarial vasculitis, Clin Dermatol 17:565-569, 1999). Since urticarial vasculitis is characterized by a variety of cutaneous, systemic, and serological features, different names of this disorder exist in the literature (Wisnieski JJ, Urticarial vasculitis, Curr Opin Rheumatol 12:24-31, 2000). A biopsy of an active lesion remains the gold standard for the diagnosis of urticarial vasculitis.

Abundance of the long pentraxin PTX3 at sites of leukocytoclastic lesions in patients with small-vessel vasculitis.

OBJECTIVE: The prototypical tissue pentraxin PTX3 inhibits phagocytosis of late apoptotic polymorphonuclear leukocytes (PMNs) by macrophages. Levels of PTX3 parallel disease activity in small-vessel vasculitis. Small-vessel vasculitis is often characterized by leukocytoclasia, a phenomenon of accumulation of nuclear remnants from unscavenged PMNs in or near the vessel wall. We therefore hypothesized that PTX3 accumulates at sites of leukocytoclastic vasculitis and, as such, is a key factor for the induction of leukocytoclasis. METHODS: We examined skin biopsy samples from 13 patients with small-vessel vasculitis and from 4 healthy and 3 inflammatory skin disease controls. Biopsy tissues, characterized histopathologically as leukocytoclastic vasculitis, were studied for the presence of PTX3 using rabbit anti-PTX3 polyclonal antibodies. Sections were scored morphometrically for leukocytoclastic infiltrates in conjunction with PTX3 staining. Morphometric scores were expressed as percentages of staining of the total tissue area. RESULTS: Biopsy specimens from patients with leukocytoclastic vasculitis revealed an abundant up-regulation of PTX3 at sites of leukocytoclastic infiltrates. Significantly more PTX3 was found in tissues from the 13 patients with vasculitis (mean +/- SEM 48.9 +/- 6.1%) than in tissues from the 7 controls (4.5 +/- 2.7%) (P = 0.0003). PTX3 was localized around vessels, as well as spread diffusely throughout the tissue. CONCLUSION: PTX3 is abundantly present at sites of leukocytoclastic infiltrates in patients with small-vessel vasculitis, but not in controls. Since PTX3 inhibits phagocytosis of late apoptotic PMNs by macrophages and is strongly up-regulated at sites of leukocytoclastic infiltration, PTX3 is a candidate factor in the phenomenon of leukocytoclasia in small-vessel vasculitis.