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Objectives: The prevalence and definition of benign multiple sclerosis (BMS) remain controversial. Most definitions are based on the Expanded Disability Status Scale (EDSS), not encompassing the wider impact of disease. The explanation for favourable outcomes remains unclear. We aim to provide a detailed characterisation of patients with low EDSS scores at long disease durations., Methods: We screened a population-based registry containing 3062 people with MS to identify individuals with unlimited walking ability at disease durations >15 years. A representative cohort underwent detailed clinical assessment and classified as having BMS according to EDSS score <3, no significant fatigue, mood disturbance, cognitive impairment or disrupted employment, and had not received a disease-modifying therapy. We determined patient-reported perceptions of MS status and made comparisons with EDSS-based definitions., Results: Of 1049 patients with disease duration of >15 years, 200 (19.1%) had most recent EDSS score <4.0. Detailed contemporary clinical assessment of a representative sample of 60 of these patients revealed 48 (80%) had an EDSS score of <4.0, 35 (58%) <3.0 and 16 (27%) <2.0. Only nine (15%) fulfilled our criteria for BMS; impaired cognition (57%) and effects on employment (52%) the most common causes for exclusion. Meanwhile, 33/60 (69%) patients considered their disease benign. Population frequency for BMS was estimated at 2.9% (95% CI 2.0 to 4.1)., Conclusions: Comprehensive assessment reveals a small minority of people with MS who appear genuinely benign after 15 years. Study of such individuals may uncover insights about disease pathogenesis. However, discrepancy between patient perception and clinician perception of BMS undermines use of the term 'benign' in clinical settings., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

This study investigated the action of aqueous extracts of airborne grain dusts on the human alternative and classical complement pathways. Extracts were shown to consume hemolytic complement in vitro in a dose-dependent manner. No relationship was determined between complement activity ranking and either protein or endotoxin levels. Differential serum chelation with EDTA or EGTA showed that the alternative pathways were activated, while hemolytic titers of the early complement components (C1, C4, C2 and C3) showed that the classical pathway was also involved. Extract-treated sera were chemotactic for human polymorphonuclear leukocytes and complement was required. The in vitro data suggest the potential for the in vivo contribution of the activation of the complement cascade (by either pathway) in eliciting pulmonary pathophysiology after the inhalation of airborne grain dusts.

Commercial allergen extract preparations of whole cereal grains were examined in vitro for their reactivity with the human haemolytic complement cascade. Total haemolytic complement was consumed in a dose-dependent manner which did not correlate with the protein nitrogen content or bacterial endotoxin contamination of the extracts. Alternative pathway activation was shown by C3 conversion in the presence of EGTA while classical complement components C1, C4 and C2 were also much decreased in serum which was free of detectable specific antibody. Very small amounts of allergen extract initiated the formation of complement-dependent factors which were chemotactic for human polymorphonuclear leucocytes. These data suggest a potential for complement activation in vivo by ingestion, inhalation, or injection of cereal grain products.

One hundred and seventy-four unrelated white patients with biopsied and clinically diagnosed sarcoidosis and a reference population of 97 were tested for HLA antigens. Selected comparisons showed a statistically significant association of HLA-B8 with the sarcoidosis group (28.9%) when compared to the reference group (15.5%).

Cotton grown in Stoneville, Mississippi and harvested by three different methods was examined for anticomplementary activity in human serum in vivo. Subjects exposed to cotton dust in a model cardroom for six hours showed changes in C3c and CH50 after exposure to closed boll harvested, bract removed cotton dust when compared with a group of normal, unexposed controls. Decreases in C3c, :C4, and C3A were associated with decreases in FEV1 after exposure to closed boll harvested bract intact cotton dust. The data from this preliminary study suggest in vivo associations between inhalation of cotton dusts and complement which appear to be independent of endotoxin contamination. These findings suggest a relationship between cotton dust inhalation and complement-mediated respiratory impairment.

Sera from 84 white patients with inactive sarcoidosis were analyzed for immunoglobulins, complement, autoantibodies, alpha 1-antitrypsin and lysozyme. The levels of serum factors were compared with levels in serum from a reference population which was matched for age, sex, ethnic background and geographic location. IgG, IgA, IgD, and C3 levels were similar for both groups, as were frequencies of rheumatoid factor, antinuclear antibody and anti-DNA antibody. Lysozyme levels were significantly lower in the inactive sarcoidosis group but the acute phase reactants alpha 1-antitrypsin, IgM as well as complement consumption were increased. The data suggest that the underlying etiological events of sarcoidosis continue, albeit at a subclinical level.

Epidemiological investigations of grain workers have suggested the presence of biological hazards in terminal grain elevators. Immunological assessments of the involved individuals, however, have produced inconclusive results. We have recently demonstrated in vitro a potential biological mechanism which could occur in vivo upon inhaling airborne graon dust, thereby constituting a potential inflammatory insult to the respiratory tracts of grain workers. Airborne dusts of similar size distributions generated by transporting grain in terminal grain elevators have been shown to activate the alternative pathway of complement in precipitin-negative pooled normal human serum. These dusts consumed hemolytic complement in a dose-response manner as quantified by both CH100 immunodiffusion and CH50 tube methods. The proactivator of C3 was converted to the activator form in the presence of the chelator EGTA, but conversion was prevented by EDTA. Likewise, serum from guinea pigs genetically deficient in C4, thereby lacking a functional classical complement pathway, showed complement consumption by grain dusts via the alternative pathway. Relative CH50 toxicity ranking of the various dusts was found to be unrelated to the amount of endotoxin present. Of interest, aged settled dust (20-30 years) remained relatively active against the alternative complement pathway as did 15 min aqueous extracts of ground whole rye.

Laboratory rabbits were exposed for 60 min to aerosols of dry cardroom cotton dust 4 days/wk (Tuesday through Friday) for 15 consecutive weeks. As a parameter of pulmonary pathophysiology, arterial blood gases were monitored with time after challenge. Post-exposure blood gas analyses at 1 hr showed progressive decreases in arterial oxygen tension, with concommitant increases in arterial carbon dioxide tension and the alveolar-arterial oxygen gradient. These responses appeared to result from acute reversible airway obstruction which caused unequal gas distribution and ventilation-perfusion inequalities. When a group of proven responder rabbits was challenged with cardroom cotton dust which was first treated in a manner which paralleled the preparation of medical grade cotton, only minor decreases in arterial oxygen tension were observed. The data suggest that some, as yet undefined, agent(s) which was removed by the treatment was responsible for inciting the observed pathophysiology.

The pathogenesis of byssinosis has been attributed to several different immunopathologic mechanisms, including a type III (immune complex) pulmonary injury. To further examine this type III theory, sera (Monday preshift) from 59 cotton textile workers were examined by gel diffusion and counterimmunoelectrophoresis for precipitating antibodies to aqueous extracts of cotton bract, carpels, stems, leaves, immature cotton bract, carpels, stems, leaves, immature cotton lint, and cardroom cotton dust. Sera were also collected from 35 nonexposed normal volunteers and examined similarly. No true precipitating antibodies to these extracts could be detected in any of the control or worker serum samples. The aqueous extracts of cardroom cotton dust and cotton stems were found to contain naturally occurring components that precipitated (in agarose gel) beta-lipoprotein and gamma-globulins (mostly IgG) in a nonimmunologic manner. Sera from normal human controls and cotton textile workers all produced identical patterns of reaction with these two extracts. Treatment of these extracts with polyvinylpolypyrrolidone, a specific insoluble adsorbent for polyphenolic tannins, eliminated this pseudoimmune reaction. Although the role this pseudoimmune reaction may play in the pathogenesis of byssinosis is still unknown, it demonstrates the problems associated with laboratory-based investigations of the immunologic aspects of byssinosis.

Ground whole rye and airborne rye dust of comparable size distribution were tested for their ability to activate the complement cascade via the alternative pathway. Precipitin-negative pooled normal human serum was incubated with increasing amounts of the two rye dusts. Electrophoresis of the resultant supernatant fluids demonstrated the conversion of the proactivator of the third component of complement to the gamma-migrating activator of the third component. This activation was completely prevented by pre-treating the serum with the chelator EDTA, while pre-treatment with EGTA allowed suboptimal arc conversion, strongly implying that complement was activated via the alternative pathway. Quantification of the supernanant fluids showed dose-dependent complement consumption as defined by both CH100 immunodiffusion and CH50 tube haemolytic techniques. Airborne rye dust showed a greater quantitative potential than ground whole rye for activating the alternative pathway. These results indicate the possibility of the direct action of airborne organic dusts on the induction of inflammatory sequelae in the lungs of both sensitized and unsensitized individuals.

Serum from 109 coal workers with simple pneumoconiosis, 114 with progressive massive fibrosis, and 130 with normal chest radiographics as control subjects was examined for rheumatoid and antinuclear factors, and antibodies against both native human IgG and Mycobacterium tuberculosis. A significantly greater prevalence of autoantibodies was observed in subjects with pneumoconiosis than in control subjects; however, a rheumatoid factor prevalence of 16% with observed inthe control subjects. No serologic differences were observed between subjects with simple pneumoconiosis and those with progressive massive fibrosis.

Settled grain dust was collected from several active grain elevators in the Superior-Duluth areas of the United States. Particle size distribution (47% less than 5 micrometer) and endotoxin contamination (429 ng/gm) of the dust were similar to those reported for the airborne parent dust. Human complement uas activated in vitro in a dose-response manner which could be quantified. This hemolytic consumption was via the alternative pathway as defined by ethylenediaminetertraacetic acid/ethylene-glycol-bis-(beta-amino-ethyl ether) N,N'-tetraacetic acid (EDTA/EGTA) differential serum chelation, factor B conversion, and complement reductions in serum from guinea pigs deficient in C4. It is proposed that continuous low-dose exposure to aerosolized, biologically active rafter dust could contribute to the respiratory insult of grain workers.

Pulmonary reactions to fungal spores constitute an important aspect of occupational pneumoconioses. Experimental models using aerosols of Aspergillus terreus spores produce an acute, complement dependent, hypoxic reaction in rabbits. The purpose of this study was to explore the possible role of the alveolar macrophage in initiating this reaction. Rabbits and rats were intratracheally injected with Aspergillus spores and the fate of the spores was studied at various times thereafter by light and scanning electron microscopy complemented by heavy metal staining and backscattered electron imaging. The uptake of spores by macrophages on the surface of the alveoli and airways was extremely rapid and was virtually complete by 3 hrs. Very few polymorphonuclear leukocytes were seen in the lungs of exposed animals. Penetration of the lung epithelium by spores was minimal and was not directly observed. Alveolar clearance followed by mucociliary clearance of the spores was observed in the rats. Failure of the clearance mechanisms at the level of the respiratory bronchiole produced necrotising lesions that contained numerous free spores. This study illustrates the value of heavy metal stains combined with backscattered electron imaging for observing surface and subsurface features in biological tissues.