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To define the clinical, serological, and muscle histopathological characteristics, as well as treatment outcomes, of patients with anti‐Ha antibody. We performed a retrospective analysis of clinical, serological, and pathological data and long‐term treatment outcomes of anti‐Ha patients between January 2005 and July 2023 at our center. Anti‐Ha antibody was identified by immunoblot and reconfirmed by immunoprecipitation. Of the 570 patients with idiopathic inflammatory myopathies, 17 (3.0%) were found to be anti‐Ha positive, of whom 5 (29.4%) were also positive for another myositis‐specific antibody (MSA). All patients with anti‐Ha antibody as the single MSA (12/17, 70.6%) had clinical and histopathological evidence of muscle damage. Skin lesions were identified in nine of them (75%), while both interstitial lung disease and Raynaud's phenomenon were only seen in four patients. A necrotizing myopathy without a perifascicular pattern was the most common pathological manifestation (50%). Perifascicular necrosis (PFN) and myofiber major histocompatibility complex class‐II expression were observed only in one and four patients, respectively. Muscle weakness relapse was reported in five patients, and skin rashes worsening were observed in one patient. Most of the anti‐Ha patients (66.7%) finally achieved a favorable outcome at last follow‐up. Anti‐Ha antibody might not be as rare as previously thought and may coexist with other MSAs. Muscle damage is the most common manifestation in anti‐Ha patients, while extra‐muscular symptoms except for the cutaneous manifestations are unusual. The histopathological features varied with a predominance of necrotizing myopathy without PFN. These patients often finally had favorable outcomes, although relapses often occur. A necrotizing myopathy without a perifascicular pattern is the most common pathological manifestation of anti‐Ha ASS.

[This corrects the article DOI: 10.3389/fimmu.2025.1614777.].

We report on a 38-year-old patient who presented with rapidly progressive interstitial lung disease (ILD), without any signs of muscular involvement. Antinuclear antibody testing by indirect immunofluorescence revealed a nuclear titer of 1:320 with a fine speckled and a cytoplasmic titer of 1:1’280 with a fine speckled pattern. Subsequent myositis-specific and myositis-associated antibody tests with commercial multiplex dot-immunoassays showed a strong positive result for anti-Ha antibodies, also confirmed by protein immunoprecipitation, establishing the diagnosis of anti-synthetase syndrome with associated ILD. Despite initial improvement after treatment with intravenous cyclophosphamide and high dose steroids, he relapsed shortly after, with additional muscular symptoms. Subsequent escalation of therapy with rituximab resulted in sustained remission. Considering the scarcity of data about the clinical presentation and prognosis of patients with anti-Ha antibodies, our report provides additional information on diagnostic challenges and therapeutic response in these patients.

Anti-synthetase syndrome (ASS) is a rare autoimmune myopathy, frequently associated with interstitial lung disease, and is characterized by the presence of anti-aminoacyl tRNA synthetase (ARS) antibodies. However, there have been limited reports of cases exhibiting positive anti-Ha antibodies. This study presents a retrospective analysis of the clinical data from a patient with an acute exacerbation of ASS who tested positive for anti-Ha antibodies. This patient initially presented with interstitial pneumonia. The initial anti-infective treatment was ineffective; however, symptoms improved following the addition of corticosteroids. Upon discontinuation of corticosteroids, the patient experienced a recurrence of cough, progressive worsening of dyspnea, and developed lower general weakness. Comprehensive autoantibody testing revealed positivity for anti-Ha antibodies, and MRI of the lower limbs indicated soft tissue edema. The patient was ultimately diagnosed with ASS with interstitial lung disease. Treatment with methylprednisolone pulse therapy, combined with cyclophosphamide, tacrolimus, tofacitinib citrate, and pirfenidone, led to an improvement in the patient's condition, resulting in discharge. Post-discharge, the patient was maintained on regular oral prednisone, nintedanib, and tofacitinib. Follow-up to date has shown a stable condition, with resolution of pulmonary lesions observed upon re-examination. Anti-Ha antibody is one of the specific antibodies associated with ASS, yet its positive rate remains exceedingly low. This case represents the first reported instance of an anti-Ha antibody-positive ASS in China. Misdiagnosis and missed diagnosis are prevalent in clinical practice, underscoring the importance of screening for autoantibodies when patients present with acute, unexplained interstitial lung changes and a poor response to anti-infective treatment. Furthermore, interstitial lung disease is the most common extra-muscular clinical manifestation observed in ASS patients. Differentiating between acute exacerbations of pulmonary infections and interstitial lung disease associated with rheumatic diseases poses a significant challenge, as both can occur concurrently. Therefore, during diagnosis and treatment, it is crucial to consider not only infections but also to identify the underlying causes of worsening lung lesions.

(1) Background: Avian influenza viruses (AIVs) promptly evade preexisting immunity by constantly altering the immunodominant neutralizing antibody epitopes (antigenic drift) or by procuring new envelope serotypes (antigenic shift). As a consequence, the majority of antibodies elicited by infection or vaccination protect only against closely related strains. The immunodominance of the globular head of the main glycoprotein has been shown to mask the immunogenicity of the conserved regions located within the hemagglutinin (HA) protein. It has been shown that the broadly neutralizing universal antibodies recognize the HA2 domain in headless hemagglutinin (HA-stalk). Therefore, the HA-stalk is a highly conserved antigen, which makes it a good candidate to be used in universal vaccine development against AIVs. (2) Methods: Sf9 insect cells were used to produce triple H5N1/NA-HA-M1 influenza virus-like particles (VLPs) via co-expression of neuraminidase, hemagglutinin and matrix proteins from a tricistronic expression cassette. Purified influenza VLPs were used to immunize broiler hens. An in-depth characterization of the immune response was performed with an emphasis on the pool of elicited universal antibodies. (3) Results: Our findings suggest, that after vaccination with triple H5N1/NA-HA-M1 VLPs, hens generate a pool of broad-spectrum universal anti-HA-stalk antibodies. Furthermore, these universal antibodies are able to recognize the mammalian-derived HA-stalk recombinant proteins from homologous H5N1 and heterologous H7N9 AIVs as well as from the heterosubtypic human H1N1 influenza strain. (4) Conclusions: Our findings may suggest that highly pathogenic avian influenza H5 HA protein contain functional epitopes that are attractive targets for the generation of broad-spectrum antibodies against AIVs in their native hosts.

The stalk domain of influenza virus envelope glycoprotein hemagglutinin (HA) constitutes the axis connecting the head and transmembrane domains, and plays pivotal roles in conformational rearrangements of HA for virus infection. Here we characterized molecular interactions between the anti-HA stalk neutralization antibody F11 and influenza A(H1N1)pdm09 HA to understand the structural basis of the actions and modifications of this antibody. In silico structural analyses using a model of the trimeric HA ectodomain indicated that the F11 Fab fragment has physicochemical properties, allowing it to crosslink two HA monomers by binding to a region near the proteolytic cleavage site of the stalk domain. Interestingly, the F11 binding allosterically caused a marked suppression of the structural dynamics of the HA cleavage loop and flanking regions. Structure-guided mutagenesis of the F11 antibody revealed a critical residue in the F11 light chain for the F11-mediated neutralization. Finally, the mutagenesis led to identification of a unique F11 derivative that can neutralize both F11-sensitive and F11-resistant A(H1N1)pdm09 viruses. These results raise the possibility that F11 sterically and physically disturbs proteolytic cleavage of HA for the ordered conformational rearrangements and suggest that in silico guiding experiments can be useful to create anti-HA stalk antibodies with new phenotypes.

Connective tissue diseases (CTDs) are an important secondary cause of interstitial lung disease (ILD). If a CTD is suspected, clinicians are recommended to perform autoantibody testing, including for myositis autoantibodies. In this study, the prevalence and clinical associations of novel myositis autoantibodies in ILD are presented. A total of 1194 patients with ILD and 116 healthy subjects were tested for antibodies specific for Ks, Ha, Zoα, and cN1A with a line-blot assay on serum available at the time of diagnosis. Autoantibodies were demonstrated in 63 (5.3%) patients and one (0.9%) healthy control (p = 0.035). Autoantibodies were found more frequently in females (p = 0.042) and patients without a histological and/or radiological usual interstitial pneumonia (UIP; p = 0.010) and a trend towards CTD-ILDs (8.4%) was seen compared with other ILDs (4.9%; p = 0.090). The prevalence of antibodies specific for Ks, Ha, Zoα, and cN1A was, respectively, 1.3%, 2.0%, 1.4%, and 0.9% in ILD. Anti-Ha and Anti-Ks were observed in males with unclassifiable idiopathic interstitial pneumonia (unclassifiable IIP), hypersensitivity pneumonitis (HP), and various CTD-ILDs, whereas anti-cN1A was seen in females with antisynthetase syndrome (ASS), HP, and idiopathic pulmonary fibrosis (IPF). Anti-Zoα was associated with CTD-ILD (OR 2.5; 95%CI 1.11–5.61; p = 0.027). In conclusion, a relatively high prevalence of previously unknown myositis autoantibodies was found in a large cohort of various ILDs. Our results contribute to the awareness that circulating autoantibodies can be found in ILDs with or without established CTD. Whether these antibodies have to be added to the standard set of autoantibodies analysed in conventional myositis blot assays for diagnostic purposes in clinical ILD care requires further study.

Influenza virus infections pre-dispose an individual to secondary pneumococcal infections, which represent a serious public health concern. Matching influenza vaccination was demonstrated helpful in preventing postinfluenza bacterial infections and associated illnesses in humans. Yet, the impact of influenza hemagglutinin (HA)-specific immunity alone in this dual-infection scenario remains elusive. In the present study, we assessed the protective effect of neutralizing and non-neutralizing anti-hemagglutinin immunity in a BALB/c influenza-pneumococcus superinfection model. Our immunogens were insect cell-expressed hemagglutinin-Gag virus-like particles that had been differentially-treated for the inactivation of bioprocess-related baculovirus impurities. We evaluated the potential of several formulations to restrain the primary infection with vaccine-matched or -mismatched influenza strains and secondary bacterial replication. In addition, we investigated the effect of anti-HA immunity on the interferon status in mouse lungs prior to bacterial challenge. In our experimental setup, neutralizing anti-HA immunity provided significant but incomplete protection from postinfluenza bacterial superinfection, despite effective control of viral replication. In view of this, it was surprising to observe a survival advantage with non-neutralizing adaptive immunity when using a heterologous viral challenge strain. Our findings suggest that both neutralizing and non-neutralizing anti-HA immunity can reduce disease and mortality caused by postinfluenza pneumococcal infections.

A phase IIa clinical trial shows that the administration of the broadly neutralizing antibody 3BNC117 delays viral rebound following the discontinuation of antiretroviral therapy in patients who were chronically infected with HIV-1. Super anti-HIV antibody tested A phase IIa clinical trial shows that the administration of the broadly neutralizing antibody 3BNC117, which targets the CD4 binding site of the HIV-1 Env protein, delays viral rebound following the discontinuation of antiretroviral therapy in patients who were chronically infected with HIV-1. The authors conclude that 3BNC117 effectively blocks emergence of antibody-sensitive viruses from HIV-1 reservoirs during analytical treatment interruption, a finding that could have significant implications for HIV-1 treatment initiatives. Interruption of combination antiretroviral therapy (ART) in HIV-1-infected individuals leads to rapid viral rebound. Here we report the results of a phase IIa open label clinical trial evaluating 3BNC117, a broad and potent neutralizing antibody (bNAb) against the CD4 binding site of HIV-1 Env 1 , in the setting of analytical treatment interruption (ATI) in 13 HIV-1-infected individuals. Participants with 3BNC117-sensitive virus outgrowth cultures were enrolled. Two or four 30 mg/kg infusions of 3BNC117, separated by 3 or 2 weeks, respectively, were generally well tolerated. The infusions were associated with a delay in viral rebound for 5-9 weeks after 2 infusions, and up to 19 weeks after 4 infusions, or an average of 6.7 and 9.9 weeks respectively, compared with 2.6 weeks for historical controls (p=<1e-5). Rebound viruses arose predominantly from a single provirus. In most individuals, emerging viruses showed increased resistance indicating escape. However, 30% of participants remained suppressed until antibody concentrations waned below 20 μg/ml, and the viruses emerging in all but one of these individuals showed no apparent resistance to 3BCN117, suggesting failure to escape over a period of 9-19 weeks. We conclude that administration of 3BNC117 exerts strong selective pressure on HIV-1 emerging from latent reservoirs during ATI in humans.

In this phase 2, randomized, placebo-controlled trial of 111 patients who had Behçet's syndrome with oral ulcers, apremilast, an oral phosphodiesterase-4 inhibitor that modulates several inflammatory pathways, reduced the number of ulcers and pain from ulcers at 12 weeks. The mucocutaneous lesions of Behçet’s syndrome include oral ulcers, genital ulcers, and papulopustular and nodular lesions. Recurrent oral ulcers can be disabling and have a substantial effect on quality of life. The current first-line therapy for the mucocutaneous lesions of Behçet’s syndrome includes colchicine and topical agents (e.g., glucocorticoids). 1 The efficacy of colchicine has been debated. 2 – 4 For lesions that are resistant to these treatments, azathioprine, interferon-α, thalidomide, and tumor necrosis factor α (TNF-α) antagonists are prescribed. There remains a need for a safe and effective treatment, and any new drug that is effective against oral ulcers (the hallmark lesion . . .