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PubMed1986

The relationship between bronchoalveolar neutrophil recruitment and bronchoconstriction induced by a soluble extract of cotton bracts.

Byssinosis is characterized by an obstructive bronchitis in some workers exposed to cotton dust. Mechanisms of airway alterations induced by cotton dust are unknown. To study mechanisms of these alterations, we administered an aqueous extract of cotton bract (CBE) to normal human subjects. After CBE inhalation, we demonstrated reproducible reductions in flow rates of variable magnitude. The percentage of polymorphonuclear leukocytes (PMN) recovered by bronchoalveolar lavage (BAL) and total PMN per milliliter BAL fluid were increased after challenge with CBE, and these parameters were correlated (r = 0.556 and r = 0.553, respectively) with the degree of bronchoconstriction induced by CBE. In addition, chemotactic factors for PMN were noted in BAL fluid and in supernatant from BAL cell cultures. The degree of BAL fluid chemotactic activity correlated with the degree of bronchoconstriction induced by CBE. Assessment of molecular sieve column effluent demonstrated BAL fluid to have 3 distinct peaks of chemotactic activity (approximate molecular weight, greater than 25,000, 10,000, and less than 1,000 daltons) and cell culture supernatant to contain 1 peak (approximate MW, 10,000 daltons). Complement activation as one source of BAL chemotactic activity was suggested by almost complete inhibition of BAL chemotactic activity after incubation with antibody to the fifth component of complement (C5) and detection of C5a des Arg in BAL fluid from some subjects challenged with CBE. These findings suggest that exposure of volunteer subjects to CBE results in a bronchoalveolar inflammatory response related to both complement activation and chemotactic factor synthesis by luminal cells.

Adult↗

PubMed1994

Complement activation and hemodynamic changes following intravenous administration of phosphorothioate oligonucleotides in the monkey.

Rapid intravenous infusion of GEM 91, a 25-mer phosphorothioate oligonucleotide complementary to the gag site of HIV, in the monkey produces transient decreases in peripheral total WBC and neutrophil counts, hemoconcentration, and a brief increase followed by a prolonged decrease in arterial blood pressure. These changes are preceded by and are likely mediated by activation of C5 complement. These effects are dose and infusion rate dependent and can be avoided by administering GEM 91 by slow intravenous infusion. Similar hemodynamic effects are produced with rapid intravenous infusion of other phosphorothioate oligonucleotides varying in length from 20- to 33-mer, and are, therefore, not sequence specific but a property of this chemical structure.

Animals↗

PubMed1974

Arthritis, deformities, and runting in C5-deficient mice injected with human rheumatoid arthritis synovium.

The pathogenesis of rheumatoid arthritis might be more easily understood and the efficacy of therapeutic measures might be more accurately assessed if a convenient animal replica of this disease were available for laboratory study. Intraperitoneal injection of homogenates of inflamed synovium taken at operation from patients with rheumatoid arthritis produces inflammatory swelling and deformity in the tail and extremities of a proportion of injected mice from a complement (C5)-deficient inbred strain. Swelling of the paws leads to limping of the affected mice. The lesions are transmissible from generation to generation. The results support the theory of a transmissible agent in the inflamed synovium of rheumatoid arthritis patients.

Animals↗

PubMed1982

Mechanisms of protective immunity against Schistosoma mansoni infection in mice vaccinated with irradiated cercariae. II. Analysis of immunity in hosts deficient in T lymphocytes, B lymphocytes, or complement.

Laboratory mice with genetic or induced immunodeficiencies were vaccinated with irradiated cercariae of Schistosoma mansoni and assayed 4 wk later for their resistance to challenge infection. Athymic nude mice failed to develop immunity to challenge or detectable antibody responses to schistosomula, whereas heterozygote (nu/+) controls and nude mice with thymus grafts displayed highly significant levels of resistance and anti-schistosomulum antibody. Similarly, no resistance or antibody production as observed in vaccinated mice that had been made deficient in B lymphocytes by the injection of anti-mu-chain antisera from birth. In contrast, normal levels of vaccine-induced resistance were observed in mice genetically deficient in the fifth component of complement (C5) and in mice decomplemented before challenge by treatment with cobra venom factor. These results indicate that the resistance to challenge infection induced by irradiated cercariae is both thymus and B lymphocyte dependent and therefore is likely to result from specific immune responses directed against schistosome worms. The data also argue against a role for complement in the effector mechanism of vaccine-induced immunity.

Animals↗

PubMed1982

In vitro kinetics of phagocytosis and intracellular killing of gonococci by peritoneal macrophages from mice deficient in complement component 5.

Unstimulated resident peritoneal macrophages were harvested from complement-sufficient (C5+) and complement-deficient (C5-) mice by peritoneal lavage and cultured for 14 h. Adherence to cover slips was determined, and the monolayer was infected with transparent T1 gonococci. At various times after infection, the macrophages were observed for both attachment and phagocytosis of the gonococci by scanning and transmission electron microscopy. this analysis indicated that C5+ macrophages were capable of immediate phagocytosis of gonococci, with maximal phagocytosis occurring by 60 to 90 min. In contrast, C5- macrophages had a greater lag time before initiation of phagocytosis; this event was started by 30 min and completed by 90 min. The intracellular gonococci which were phagocytized by either C5+ or C5- mice were completely killed after 30 min of incubation. It appears that C5- mice are at a disadvantage in the early kinetics of the phagocytosis of gonococci, but that this does not affect the ultimate intracellular destruction of gonococci.

Adhesiveness↗

PubMed2002

Increased severity of experimental allergic encephalomyelitis in lyn-/- mice in the absence of elevated proinflammatory cytokine response in the central nervous system.

lyn, a member of the src kinase family, is an important signaling molecule in B cells. lyn(-/-) mice display hyperactive B-1 cells and IgM hyperglobulinemia. The role of lyn on T cell function and development of Th1-mediated inflammatory disease is not known. Therefore, we examined the effect of disruption of the lyn gene on the development of experimental allergic encephalomyelitis (EAE), a well-established Th1-mediated autoimmune disease. Following immunization with myelin oligodendrocyte protein (MOG) p35-55, lyn(-/-) mice had higher clinical and pathological severity scores of EAE when compared with wild type (WT). The increase in the severity of EAE in lyn(-/-) mice was not associated with a commensurate increase in the production of proinflammatory cytokines in the CNS. lyn(-/-) mice with EAE showed elevation in serum anti-IgM MOG Ab levels over that seen in WT mice, along with a modest increase in the mRNA levels of complement C5 and its receptor, C5aR, in the spinal cord. Transfer of serum from MOG-immunized lyn(-/-) mice worsened EAE in WT mice, suggesting a pathogenic role for anti-MOG IgM Abs in EAE. These observations underscore the potential role of lyn in regulation of Th1-mediated disease and the role of autoantibodies and complement in the development of EAE.

Amino Acid Sequence↗

PubMed1988

Protective mechanism of the immune response to a ribosomal vaccine from Pseudomonas aeruginosa. I. In vivo protection studies in compromised animal models.

Studies of the protective activity of a ribosomal vaccine from Pseudomonas aeruginosa in various immunocompromised animal models were performed. The results obtained demonstrated that the vaccine was highly effective in complement (C5)-deficient mice, C3-deficient (cobra venom factor-treated) mice, and leukopenic mice in providing protection against lethal infection with P. aeruginosa. Passive immunization with specific antiserum to the ribosomal vaccine was also effective in leukopenic mice. In mice that were both C5-deficient and leukopenic, the vaccine did not protect mice against lethal infection, but did prolong their survival, whereas in C3-deficient, leukopenic mice significantly enhanced protection was observed. These results were interpreted to suggest the involvement of multiple factors in the protective immune response to the vaccine, including the bactericidal and opsonic activities of specific antibody plus complement and the phagocytic activity of polymorphonuclear leukocytes with opsonized bacteria. Compensation for deficiencies in some of these factors can be obtained by enhancement of other factors through active or passive immunization.

Animals↗

PubMed1975

Trypsin-activated complex of human factor B with cobra venom factor (CVF), cleaving C3 and C5 and generating a lytic factor for unsensitized guinea pig erythrocytes. I. Generation of the activated complex.

A complex formed between cobra venom factor (CVF) and isolated human factor B (B) was found to be converted by trypsin to a stable enzyme, CVF-B which cleaved the third component (C3) and the fifth component (C5) of human complement. The formation of CVF-B by trypsin required divalent cations, whereas the formation of the lytic factor from human serum occurred even in the presence of EDTA. CVF-B purified by gel filtration could initiate the hemolysis of unsensitized guinea pig erythrocytes when incubated with human complement components C5 to C9 in 0.01 M EDTA buffer. C3 was not required for the lysis of guinea pig erythrocytes initiated by CVF-B because of the beta1C precipitation line formed between human serum and anti-beta1C antibody did not inhibit the hemolysis by CVF-B in agarose gel. Treatment of beta1C and beta1F globulins in whole human serum with CVF-B in the presence of 0.01 M EDTA converted them to components with higher mobilities on immunoelectrophoresis.

ABO Blood-Group System↗

PubMed2003

Relationship between complement components C4A and C4B diversities and two TNFA promoter polymorphisms in two healthy Caucasian populations.

The RP-C4-CYP21-TNX (RCCX) modules and the tumor necrosis factor (TNF) gene cluster are probably the most polymorphic genomic regions in the human central major histocompatibility complex (MHC). Using definitive methods for genotypic and phenotypic analyses of complement components C4A and C4B, determination of the RCCX length variants, and SSP-PCR/RFLP analyses of TNFA promoter polymorphisms at positions -308 and -238, we studied the complex relationships between the C4 and TNFA polymorphisms in two normal Caucasian populations. The patterns of the RCCX modular structures and the allelic frequency of -308A TNFA (TNF2) were similar between the Budapest (n = 125) and the Ohio (n = 80) Caucasians. However, the frequency of the -238A allele was significantly higher in the Ohio (11.3%) than in the Budapest (1.6%) study population (p < 0.0001). Marked features were found in the RCCX length variants in the TNF2 carriers and noncarriers. Strong associations were found between the C4AQ0 B1 haplotype from the monomodular short (mono-S) RCCX structure and the TNF2 allele, and between the C4A6 B1 haplotype from the bimodular long-short (LS) structure of the RCCX and the TNFA -238A allele. However, 36%-46% of the TNF2 carriers did not associate with a mono-S in both study cohorts, and 57.1% of the TNFA -238A carriers in Ohio did not associate with C4A6, which has a defective complement C5 convertase activity. The carriers of TNF2 allele had significantly lower C4A serum concentration (0.17 +/- 0.08 g/l) than noncarriers (0.23 +/- 0.09 g/l) (p < 0.001). The lowest C4A serum levels were found in TNF2 carriers with mono-S structures (0.14 +/- 0.06 g/l). In essence, our results demonstrated the heterogeneities of the TNFA promoter polymorphisms, and the linkage disequilibrium of TNFA -308A and -238A alleles with complement C4A deficiency and impaired C4A protein function, respectively.

Blotting, Southern↗

PubMed2026

Independent prognostic value of semaphorin-4D, interleukin-1β and complement activation in newly diagnosed multiple myeloma patients.

Multiple myeloma represents a systemic disease of the bone marrow (BM) niche, in which immune and skeletal pathways are tightly interconnected. However, the independent prognostic significance of bone and immune-related markers in newly diagnosed multiple myeloma (NDMM) remains incompletely understood. Semaphorin (Sema) 4D, activin-A, and periostin ELISA, LEGENDplex™ Human Bone Metabolism Panel and proteomic analysis for novel biomarker identification were conducted in 71 consecutive samples from NDMM patients. In 25 patients, genomic analysis was performed on sorted clonal plasma cells. NDMM patients had a median age at diagnosis of 65 years and a median follow-up of 2.5 years. Interleukin (IL)-1β and Sema4D levels predicted progression-free survival (PFS), highlighting their role in disease relapse. Proteomic profiling revealed a systemic signature associated with worse prognosis, enriched in complement activation components. Complement C5 significantly affected PFS and time to progression (TTP). IL-1β and C5 predicted PFS independently of the second revision of the International Staging System (R2-ISS) stage, and a similar trend was noted for Sema4D. Myeloma bone disease (MBD) did not significantly affect overall survival, PFS, or TTP, suggesting that contemporary treatments mitigate its impact. Genomic analyses identified variants associated with inferior PFS, including HLA-DRB5 (c.300_306delinsCGGG) and HLA-DQB1 (c.317_319delinsCGG). Sema4D and the IL-1β-complement cascade emerged as key drivers of disease progression, independent of R2-ISS stage, representing potential prognostic and therapeutic targets in NDMM.

Journal Article↗

PubMed1998

Involvement of C3a and C5a in interleukin-8 secretion by human polymorphonuclear cells in response to capsular material of Cryptococcus neoformans.

In a previous paper we demonstrated that human polymorphonuclear cells (PMN) in the presence of normal human serum (NHS) secrete proinflammatory cytokines in response to Cryptococcus neoformans or its major capsular component, glucuronoxylomannan (GXM). The hypothesis that activation of the complement system could be responsible for the observed phenomenon is supported by the fact that encapsulated and acapsular C. neoformans isolates are activators of the complement system and, in particular, large encapsulated isolates are powerful activators. In the present study we demonstrate that (i) interleukin-8 (IL-8) release in response to acapsular or encapsulated strains of C. neoformans is significantly reduced in the presence of heat-inactivated serum rather than NHS and is completely abrogated in the absence of human serum; (ii) GXM-induced IL-8 release is strictly dependent on the presence of NHS, is inhibited by specific antibodies to either C3a and C5 complement components, and is completely abrogated by the combined use of these antibodies; (iii) the addition of purified C3a and C5a directly stimulates IL-8 release by PMN; and (iv) monoclonal antibody to GXM in combination with GXM or encapsulated C. neoformans potentiates IL-8 release by PMN. These data shed light on the mechanism involved in GXM-induced IL-8 secretion by PMN, provide an additional potential role for complement in the control of C. neoformans infections, and suggest a complex interplay between the complement system, humoral immunity, and cytokine regulation.

Cells, Cultured↗

PubMed2001

Zymosan enhances the immune response to DNA vaccine for human immunodeficiency virus type-1 through the activation of complement system.

In the present study, the adjuvant effect of zymosan on human immunodeficiency virus type-1 (HIV-1)-specific DNA vaccine and the mechanism of this enhancement were studied in a murine model. We coinoculated zymosan with our candidate HIV-1 specific DNA vaccine (pCMV160IIIB) into skeletal muscles of BALB/c mice. Higher levels of both humoral immune response and HIV-specific delayed-type hypersensitivity (DTH) response were observed when zymosan was coinoculated with pCMV160IIIB compared with that obtained using pCMV160IIIB alone. HIV-specific cytotoxic T lymphocyte (CTL) activity was also enhanced. This enhancing activity was suppressed when coinoculated to the fifth complement (C5)-deficient DDD and AKR mice. The enhanced activity was also suppressed when anti-C3 antibody was inoculated to mice intramuscularly. There was significant induction of immunoglobulin G2a (IgG2a) and interferon-gamma (IFN-gamma) in pCMV160IIIB vaccine with zymosan. These results suggest that zymosan-mediated DNA vaccination enhances helper T cell (Th) 1-mediated immunity. The effect is suggested to be based on the consequences of its recruitment and activation of macrophages, dendritic cells or antigen-presenting cells (APC) through complement activation, especially through the alternative pathway. Taken together, these results suggest that zymosan can be an effective immunological adjuvant in DNA vaccination against HIV-1.

AIDS Vaccines↗

PubMed2001

Structure and composition of drusen associated with glomerulonephritis: implications for the role of complement activation in drusen biogenesis.

PURPOSE: The ocular fundi of many patients with membranoproliferative glomerulonephritis type II (MPGN-II) are characterised by the presence of deposits within Bruch's membrane that resemble drusen, hallmark lesions associated with age-related macular degeneration (AMD). Glomerulonephritis (GN)-associated drusen appear at a younger age, however, than do drusen in individuals with AMD. In light of recent evidence that immune-mediated events participate in drusen biogenesis and AMD, we examined the structure and composition of drusen in eyes obtained from human donors with two distinct glomerulopathies, both of which involve complement deposition within glomeruli. These features were compared with those of drusen from patients with clinically documented AMD. METHODS: Eyes obtained from two human human donors diagnosed with membranous and post-streptococcal GN, respectively, were analysed histochemically, immunohistochemically and ultrastructurally. RESULTS: Subretinal pigment epithelial (RPE) deposits in both types of GN are numerous and indistinguishable, both structurally and compositionally, from drusen in donors with AMD. GN-associated drusen exhibit sudanophilia, bind filipin, and react with antibodies directed against vitronectin, complement C5 and C5b-9 complexes, TIMP-3 and amyloid P component. Drusen from the membranous GN donor, but not the post-streptococcal GN donor, reacted with peanut agglutinin and antibodies directed against MHC class II antigens and IgG. The ultrastructural characteristics of these deposits were also identical with those of AMD-associated drusen. CONCLUSIONS: The composition and structure of ocular drusen associated with membranous and post-streptococcal/segmental GN are generally similar to those of drusen in individuals with AMD. In view of the recent data supporting the involvement of complement activation in drusen biogenesis and the pathobiology of AMD, further studies of the biological relationships between AMD and diseases associated with complement activation are warranted.

Complement Activation↗

PubMed1989

Ba and Bb fragments of factor B activation: fragment production, biological activities, neoepitope expression and quantitation in clinical samples.

Factor B is a centrally important component of the alternative complement pathway. Alternative pathway activation results in factor B cleavage and production of the amino-terminal Ba and the carboxyl-terminal Bb fragments which have molecular weights of approximately 30,000 and 63,000 daltons, respectively. Both Ba and Bb fragments have been reported to express a variety of biological activities in vitro. Thus, binding of Ba and Bb fragments to specific B lymphocyte surface receptors modulates proliferation of prestimulated B cells. In addition, the enzymatically active Bb fragment induces activation and spreading of human and murine macrophages and monocytes as well as regulates C5a des Arg chemotactic activity. The fractional catabolic rate and metabolism of factor B in vivo is similar to that of C3, C4 and C5 complement proteins, which are among the most metabolically active plasma proteins in the circulatory system. Factor B hyperconsumption and increased catabolism, concomitant with factor B fragment production, occurs in a wide variety of diseases, including gram-negative sepsis, autoimmune diseases and burns. Measurement of alternative pathway activation in vivo has been attempted utilized a number of different techniques to quantitate factor B fragments in biological fluids. However, the recent development of enzyme immunoassays (EIA) employing monoclonal antibodies (MoAbs) reactive with factor B fragment neoepitopes provides the best approach currently available for the quantitation of factor B activation fragments. Results obtained using these new MoAb-based EIAs have indicated that factor B fragment concentrations were elevated, as compared with normal donor levels, in EDTA plasma samples obtained from patients with rheumatoid arthritis and systemic lupus erythematosus (SLE). Plasma concentrations of factor B fragments, especially Ba fragment levels, in these patients showed a positive correlation with disease activity scores. One of the highest disease activity correlations was obtained with Ba fragment measurements in SLE plasma samples. In fact, the results strongly suggested that quantitation of Ba fragment levels in SLE plasma samples more accurately reflected disease activity and was a more sensitive predictor of impending flare in these patients than any other test(s) currently available.

Antibodies, Monoclonal↗

PubMed1980

A hypocomplementemic vasculitic urticarial syndrome. Report of four new cases and definition of the disease.

We describe four new patients with a unique syndrome of persistent urticaria, with leukoclastic angiitis, severe angioedema, occasional life-threatening laryngeal edema, arthritis, arthralgia, neurologic abnormalities and pronounced persistent hypocomplementemia. The complement abnormalities involved markedly reduced levels of the Clq subunit of the first component of complement (Cl) in the presence of near normal levels of Clr and Cls subunits of Cl; modest to marked depletion of the fourth component of complement (C4), the second component of complement (C2) and the third component of complement (C3); and normal levels of the fifth through ninth components of complement (C5 through C9) and properdin factors B and D. A striking serologic abnormality found in all patients was the presence of low molecular weight (7S) proteins which precipitated with Clq in agarose gels; these previously were shown to be comprised at least in part of immunoglobulin G. The present experience is offered to help to define the clinical, histopathologic and serologic characteristics of this entity, designated hypocomplementemic vasculitic urticarial syndrome, and to emphasize its distinctiveness and prevalence.

Adult↗

PubMed1990

C5a-induced neutrophilia. A primary humoral mechanism for recruitment of neutrophils.

The leukocytosis activity of C5a was studied in a rabbit model. Blood samples were drawn for cell counts through a catheter placed in an artery of one rabbit ear after injection of either porcine or human C5a into a vein in the opposite ear. These studies indicate the potential of C5a to mobilize bone marrow neutrophils following transient C5a-induced neutropenia, based on counts of nonsegmented neutrophils. The numbers of circulating neutrophils can be selectively elevated by 300% to 400%, within 1 to 2 hours, in rabbits given only microgram quantities (1 to 5 x 10(-9) mol/l) of C5a or C5adesArg. These quantities of C5a are equivalent to 1% to 2% of complement C5 activation. The time-course of the induced neutrophilia is characteristic of C5a, increasing rapidly in the first 10 to 20 minutes after injection and attaining a maximum level at 2 to 5 hours, then decreasing slowly to normal levels over the next 4 to 6 hours. After boiling at 100 degrees C for 10 minutes, C5a (C5ades Arg) lost its leukocytosis activity, indicating that the cellular effect was not caused by endotoxin. Other known leukocytosis factors, such as epinephrine, dexamethasone, lipopolysaccharide, and the prostanoid 15(S)-15-methyl PGF2 alpha, produced a distinctly different profile of leukocyte mobilization than that of C5a. The C5a-induced neutrophilia was not inhibited by pretreating these animals with indomethacin, suggesting that it is not a prostanoid-induced effect. One hypothesis is that no secondary cellular mediator system is involved in C5a-mediated leukocytosis, but rather than C5a alone is responsible for a rapid mobilization of neutrophils from bone marrow pools, and perhaps marginated pools, following neutropenia. Circulating neutrophils are activated by C5a and thereby become deformed and adherent, leading to a neutropenia, sequestration, and depletion of cells. After the neutropenic event an immediate neutrophilic response is required for replacement of this particular cell population and to re-establish homeostasis. Therefore the role of C5a may be just as important as other known leukocytosis factors (fragments from C3, for example) in promoting complement-dependent neutrophil mobilization in response to tissue injury, infections, or extracorporeal blood treatments.

Animals↗

PubMed2001

Neutrophils in chronic obstructive pulmonary disease.

Neutrophil accumulation in the lung is a prominent feature of chronic obstructive pulmonary disease (COPD) and the activation of these cells, producing proteases and oxygen-derived free radicals, is thought to be important in the pathogenesis of the disease. An important step in recruitment is the local generation of a neutrophil chemoattractant signal which mediates the trapping and firm adhesion of rolling neutrophils on the microvascular endothelium, followed by migration via intercellular junctions. Two neutrophil chemoattractants are particularly important in this respect, C5a generated by cleavage of complement C5 in interstitial fluid, and interleukin (IL)-8 synthesized by cells in the lung, e.g. macrophages, epithelial cells, endothelial cells, smooth muscle cells and neutrophils themselves. Lipid mediators, such as leukotriene B4 (LTB4), are also potentially important. Several studies have been carried out to investigate the role of IL-8 in COPD. IL-8 has been detected in bronchoalveolar lavage fluid and sputum from such subjects and in the systemic circulation. The levels of IL-8 have been found to correlate with neutrophil numbers and markers of neutrophil activation, such as myeloperoxidase activity. Some studies have also found a correlation between IL-8 levels, neutrophil numbers and the degree of lung dysfunction. These parameters are insensitive to steroids. Thus, the mechanisms involved in neutrophil recruitment, i.e. chemoattractant secretion or action, adhesion and endothelial transmigration, are important potential targets for the development of novel therapy. The IL-8 receptors on neutrophils, CXCR1 and CXCR2, are of particular interest.

Animals↗

PubMed1985

Lambert-Eaton myasthenic syndrome.

The Lambert-Eaton myasthenic syndrome is associated in about 65% of cases with small cell carcinoma, a tumour of neurosecretory origin. It is characterised physiologically by a decrease in the nerve evoked quantal release of acetylcholine, and in the resting non-quantal release ("molecular leakage"). The associations with autoimmune disease, with other autoantibodies, with HLA-B8, and with the IgG heavy chain marker Glm (2) are consistent with an autoimmune aetiology. Clinical and electromyographic responses to plasma exchange point to a humorally mediated disorder. This has been substantiated by passive transfer of the the main electrophysiological features of LEMS to mice by daily injections of LEMS IgG. Plasma was no more effective in inducing the electrophysiological changes than the IgG fraction. The decrease in quantal content appeared closely to follow the level of human IgG in the mouse serum and complement (C5) deficient mice were as susceptible as normal controls. The principal physiological abnormalities are both Ca2+ dependent processes, suggesting that a defect in Ca2+ transport may underlie the disorder. Preliminary studies of quantal content at low Ca2+ concentrations in mice injected with LEMS IgG suggest the functional loss of 40% of Ca2+ channels. Electron microscopic freeze fracture studies in such animals show, as in the human disease, a significant reduction in the number of active zone particles which are believed to represent Ca2+ channels. Thus it seems likely that the disorder of acetylcholine release is due to an IgG antibody directed to nerve terminal determinants that include the Ca2+ channels or structures closely related to them. In cancer-associated LEMS, the autoantibody response may initially be made to similar determinants on the tumour cell membrane, cross-reactivity of the antibody with nerve terminal determinants leading to the disorder of transmitter release.

Antibodies↗