Conformational dynamics of complement protease C1r inhibitor proteins from Lyme disease- and relapsing fever-causing spirochetes.

Borrelial pathogens are vector-borne etiological agents known to cause Lyme disease, relapsing fever, and Borrelia miyamotoi disease. These spirochetes each encode several surface-localized lipoproteins that bind components of the human complement system to evade host immunity. One borrelial lipoprotein, BBK32, protects the Lyme disease spirochete from complement-mediated attack via an alpha helical C-terminal domain that interacts directly with the initiating protease of the classical complement pathway, C1r. In addition, the B. miyamotoi BBK32 orthologs FbpA and FbpB also inhibit C1r, albeit via distinct recognition mechanisms. The C1r-inhibitory activities of a third ortholog termed FbpC, which is found exclusively in relapsing fever-causing spirochetes, remains unknown. Here, we report the crystal structure of the C-terminal domain of Borrelia hermsii FbpC to a limiting resolution of 1.5 Å. We used surface plasmon resonance and assays of complement function to demonstrate that FbpC retains potent BBK32-like anticomplement activities. Based on the structure of FbpC, we hypothesized that conformational dynamics of the complement inhibitory domains of borrelial C1r inhibitors may differ. To test this, we utilized the crystal structures of the C-terminal domains of BBK32, FbpA, FbpB, and FbpC to carry out molecular dynamics simulations, which revealed borrelial C1r inhibitors adopt energetically favored open and closed states defined by two functionally critical regions. Taken together, these results advance our understanding of how protein dynamics contribute to the function of bacterial immune evasion proteins and reveal a surprising plasticity in the structures of borrelial C1r inhibitors.

Presentation of an extraordinary colic: abdominal pain as the first and only utterance of an acquired C1-inhibitor deficiency.

C1-inhibitor deficiency is a rare disease which incorporates acute self-limiting intermittent swelling of the subcutaneous tissue and mucous membranes. Attacks most frequently affect the face and/or the upper airway. Isolated angioedema of the small bowel is an uncommon manifestation and often accompanied by diagnostic delay. In the present case, abdominal pain turned out to be the first and only utterance of an acquired C1-inhibitor deficiency, secondary to a splenic marginal zone lymphoma. Imaging showed wall thickening of the small intestine, ascites and splenomegaly. The abdominal pain and intestinal wall thickening with surrounding ascites on imaging spontaneously resolved each episode within 2-3 days. Gastrointestinal manifestations of angioedema may mimic an acute abdomen, and subsequently one-third of these patients undergo unnecessary surgery prior to a definite diagnosis. This emphasises the importance of considering the diagnosis in case of an 'extraordinary colic'.

The Mortality from Hereditary Angioedema Worldwide: a Review of the Real-World Data Literature.

This study aims to review the global mortality secondary to laryngeal edema in patients diagnosed with hereditary angioedema and their relatives over the years, as well as to describe epidemiological and clinical findings associated with this outcome. An extensive search of the literature was made in PubMed, Scopus, and Embase to identify mortality rates secondary to laryngeal edema in patients with hereditary angioedema. The search was carried out in September of 2020 and in April of 2021, and keywords based on the MeSH terms were searched in three databases. The filter of language was used for finding only articles in English, and there was no limit to the year of publication. A total of twenty-three articles fulfilled the inclusion criteria for review and data extraction. The analyzed studies included 3292 patients and 411 deaths from asphyxia due to laryngeal edema. One hundred and three deaths in close relatives were described as secondary to the same cause. The main findings were summarized in tables: year and place of publication, the number of patients and deaths from laryngeal edema, patients previously diagnosed, and death age. Death rates from laryngeal edema had an average of one death for every 20 patients. Eight studies reported deaths in relatives. For every 7.4 patients in these studies, one relative died. The percentage among deaths in general associated with laryngeal edema was evaluated in three studies (32.7%, 44.4%, and 56%). The high frequency of this outcome suggests that deaths still occur, and improvement of hereditary angioedema treatment still needs to be met.

COVID-19 and hereditary angioedema: Incidence, outcomes, and mechanistic implications.

Background: Patients with hereditary angioedema (HAE) have been postulated to be at increased risk for coronavirus disease 2019 (COVID-19) infection due to inherent dysregulation of the plasma kallikrein-kinin system. Only limited data have been available to explore this hypothesis. Objective: To assess the interrelationship(s) between COVID-19 and HAE. Methods: Self-reported COVID-19 infection, complications, morbidity, and mortality were surveyed by using an online questionnaire. The participants included subjects with HAE with C1 inhibitor (C1INH) deficiency (HAE-C1INH) and subjects with HAE with normal C1-inhibitor (HAE-nl-C1INH), and household controls (normal controls). The impact of HAE medications was examined. Results: A total of 1162 participants who completed the survey were analyzed, including: 695 subjects with HAE-C1INH, 175 subjects with HAE-nl-C1INH, and 292 normal controls. The incidence of reported COVID-19 was not significantly different between the normal controls (9%) and the subjects with HAE-C1INH (11%) but was greater in the subjects with HAE-nl-C1INH (19%; p = 0.006). Obesity was positively correlated with COVID-19 across the overall population (p = 0.012), with a similar but nonsignificant trend in the subjects with HAE-C1INH. Comorbid autoimmune disease was a risk factor for COVID-19 in the subjects with HAE-C1INH (p = 0.047). COVID-19 severity and complications were similar in all the groups. Reported COVID-19 was reduced in the subjects with HAE-C1INH who received prophylactic subcutaneous C1INH (5.6%; p = 0.0371) or on-demand icatibant (7.8%; p = 0.0016). The subjects with HAE-C1INH and not on any HAE medications had an increased risk of COVID-19 compared with the normal controls (24.5%; p = 0.006). Conclusion: The subjects with HAE-C1INH who were not taking HAE medications had a significantly higher rate of reported COVID-19 infection. Subcutaneous C1INH and icatibant use were associated with a significantly reduced rate of reported COVID-19. The results implicated potential roles for the complement cascade and tissue kallikrein-kinin pathways in the pathogenesis of COVID-19 in patients with HAE-C1INH.

Anti-C1-Inhibitor Autoantibody Detection by ELISA.

Enzyme-linked immunosorbent assay (ELISA) is a quantitative analytical method used to measure the concentration of molecules in biological fluids through antigen-antibody reactions. Here we describe the measurement of anti-C1-inhibitor autoantibodies by an indirect ELISA. In this method patients' sera are incubated in a microplate coated with plasma derived C1-inhibitor.

Epigenetic alterations on C1-inhibitor expression may influence hereditary angioedema attack frequency and C4 levels: Comment on: Karagianni P, Goules AV, Tzioufas AG. Epigenetic alterations in Sjogren's syndrome patient saliva.

Epigenetic studies reveal how our genes (nature) are influenced by environment (nurture) leading to wide variability in clinical presentations, especially in autoimmune diseases. Patients with C1-inhibitor deficiency, even within the same family, have diverse clinical presentations that may reflect epigenetic control of gene expression by hormones or inflammatory signals.

Thromboembolic Risk of C1 Esterase Inhibitors: A Systematic Review on Current Evidence.

INTRODUCTION: The exact risk of developing a thromboembolic event (TEE) while using complement 1 esterase inhibitors (C1-INHs) is currently undetermined for patients with hereditary angioedema (HAE). This systematic review aimed to define the potential risk of TEEs from these agents. AREAS COVERED: This evaluation covers publications examining or mentioning the risk of TEEs in association with C1-INHs. A systematic literature search was conducted utilizing PubMed, Scopus, and ProQuest. This review utilized search results through January 2020 and followed the PRISMA recommendations for a systematic review. Articles not available in English and animal or in-vitro studies were excluded. For inclusion, studies had to be open-label, randomized-controlled, cross-sectional, or clinical observational studies. A total of 13 studies met inclusion criteria and yielded 1716 patients receiving at least one dose of C1-INH, though only 41 incidences of thrombosis were documented. EXPERT OPINION: Significant heterogeneity exists in the available literature concerning both study design and the reporting of data; therefore, interpretation of thrombotic risk is difficult. TEEs are rarely reported in the literature, and they seem unlikely to occur in patients without underlying risk factors. Important risk factors include those found in the prescribing information of C1-INHs.