RESUMO
Multiple sclerosis (MS) is a complex autoimmune disease in which both the roles of genetic susceptibility and environmental/microbial factors have been investigated. More than 200 genetic susceptibility variants have been identified along with the dysbiosis of gut microbiota, both independently have been shown to be associated with MS. We hypothesize that MS patients harboring genetic susceptibility variants along with gut microbiome dysbiosis are at a greater risk of exhibiting the disease. We investigated the genetic risk score for MS in conjunction with gut microbiota in the same cohort of 117 relapsing remitting MS (RRMS) and 26 healthy controls. DNA samples were genotyped using Illumina's Infinium Immuno array-24 v2 chip followed by calculating genetic risk score and the microbiota was determined by sequencing the V4 hypervariable region of the 16S rRNA gene. We identified two clusters of MS patients, Cluster A and B, both having a higher genetic risk score than the control group. However, the MS cases in cluster B not only had a higher genetic risk score but also showed a distinct gut microbiome than that of cluster A. Interestingly, cluster A which included both healthy control and MS cases had similar gut microbiome composition. This could be due to (i) the non-active state of the disease in that group of MS patients at the time of fecal sample collection and/or (ii) the restoration of the gut microbiome post disease modifying therapy to treat the MS. Our study showed that there seems to be an association between genetic risk score and gut microbiome dysbiosis in triggering the disease in a small cohort of MS patients. The MS Cluster A who have a higher genetic risk score but microbiome profile similar to that of healthy controls could be due to the remitting phase of the disease or due to the effect of disease modifying therapies.
Assuntos
Microbioma Gastrointestinal , Esclerose Múltipla , Humanos , Microbioma Gastrointestinal/genética , Esclerose Múltipla/genética , Disbiose/genética , Predisposição Genética para Doença , RNA Ribossômico 16S/genética , Fatores de RiscoRESUMO
The etiological complexity of multiple sclerosis, an immune-mediated, neurodegenerative disease with multifactorial etiology is still elusive because of an incomplete understanding of the complex synergy between contributing factors such as genetic susceptibility and aberrant immune response. Recently, the disease phenotypes have also been shown to be associated with dysbiosis of the gut microbiome, a dynamic reservoir of billions of microbes, their proteins and metabolites capable of mimicring the autoantigens. Microbial factors could potentially trigger the neuroinflammation and symptoms of MS. In this perspective article, we discussed how microbial molecules resulting from a leaky gut might mimic a host's autoantigen, potentially contributing to the disease disequilibrium. It further highlights the importance of targeting the gut microbiome for alternate therapeutic options for the treatment of MS.
Assuntos
Microbioma Gastrointestinal , Esclerose Múltipla , Doenças Neurodegenerativas , Autoantígenos , Disbiose/complicações , Microbioma Gastrointestinal/fisiologia , Humanos , Mimetismo Molecular , Esclerose Múltipla/microbiologiaRESUMO
OBJECTIVE: To determine, in patients identified as seropositive for neuronal voltage-gated potassium channel (VGKC) complex autoantibodies, the spectrum of clinical presentations and frequency of leucine-rich glioma-inactivated protein 1 (LGI1) and contactin-associated protein-like 2 (CASPR2) as defined antigenic neuronal targets in the VGKC macromolecular complex. DESIGN: Retrospective cohort study. SETTING: Clinical practice, Mayo Clinic Neuroimmunology Laboratory and Department of Neurology. PATIENTS: A total of 54 853 patients were evaluated, of whom 1992 were found to be VGKC complex IgG positive. RESULTS: From June 1, 2008, to June 30, 2010, comprehensive service serologic evaluation performed on 54853 patients with unexplained neurologic symptoms identified 1992 patients (4%) who were positive for VGKC complex IgG (values ≥ 0.03 nmol/L). Among 316 seropositive patients evaluated clinically at our institution, 82 (26%) were seropositive for LGI1 IgG and/or CASPR2 IgG. Of these 82 patients, 27% had low (0.03-0.09 nmol/L), 51% had medium (0.10-0.99 nmol/L), and 22% had high (≥ 1.00 nmol/L) VGKC complex IgG values. Leucine-rich glioma-inactivated protein 1 IgG positivity was associated with higher VGKC complex IgG values (P< .001) and cortical presentations (P< .001); CASPR2 IgG was associated with peripheral motor excitability (P= .009). However, neither autoantibody was pathognomonic for a specific neurologic presentation or correlated significantly with cancer. Neurologic phenotypes were diverse. Cerebrocortical manifestations (including cognitive impairment and seizures) were recorded in 76% of patients with LGI1 IgG alone (n=46) and 29% with CASPR2 IgG alone (n=28). Peripheral motor hyperexcitability was found in 21% of patients with CASPR2 IgG alone and 6.5% of patients with LGI1 IgG alone. CONCLUSIONS: The study emphasizes diverse and overlapping neurologic phenotypes across a range of VGKC complex IgG values and varying LGI1 IgG and CASPR2 IgG specificities. The frequent occurrence of LGI1 IgG and CASPR2 IgG in serum samples with low and medium VGKC complex IgG values supports the clinical significance of low values in clinical evaluation. Additional antigenic components of VGKC macromolecular complexes remain to be defined.
Assuntos
Autoanticorpos/sangue , Imunofenotipagem , Proteínas de Membrana/imunologia , Proteínas do Tecido Nervoso/imunologia , Proteínas/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Autoanticorpos/biossíntese , Doenças Autoimunes/diagnóstico , Doenças Autoimunes/imunologia , Biomarcadores/sangue , Estudos de Coortes , Feminino , Humanos , Imunofenotipagem/métodos , Peptídeos e Proteínas de Sinalização Intracelular , Masculino , Pessoa de Meia-Idade , Doenças do Sistema Nervoso/diagnóstico , Doenças do Sistema Nervoso/imunologia , Estudos Retrospectivos , Estudos Soroepidemiológicos , Adulto JovemRESUMO
OBJECTIVE: Autoantibodies targeting voltage-gated potassium channel (VGKC) complexes cause a spectrum of neuronal hyperexcitability disorders. We investigated pain as a manifestation of VGKC-complex autoimmunity. METHODS: We reviewed the prevalence and characteristics of pain in VGKC-complex-immunoglobulin G (IgG)-seropositive patients in 25 months of comprehensive service testing for neural autoantibodies, subtyped positive sera for LGI1-IgG and CASPR2-IgG specificities, and reviewed pain prevalence in autoimmune control patients. RESULTS: VGKC-complex-IgG was identified in 1,992 patients of 54,853 tested (4%). Of 316 evaluated neurologically at Mayo Clinic, 159 (50%) had pain, in isolation (28%) or with accompanying neurologic manifestations (72%), and not attributable to alternative cause. Pain was subacute in onset, chronic in course, neuropathic, nociceptive, regional, or diffuse and sometimes attributed to fibromyalgia (6%) or psychogenic cause (13%). Most patients had normal peripheral nervous system function, measured by neuropathy impairment scores and nerve conduction. Evidence of neuronal hyperexcitability (hyperhidrosis, quantitative heat-pain hyperalgesia, or electromyographic excitability) was 25-fold more common in pain patients. Pain management required multiple medications in 70% (narcotics, 30%); 13 of 16 patients reported pain relief with immunotherapy. Pain was significantly associated with CASPR2-IgG-positivity (16% positive with pain, 7% without pain; p = 0.014) but not with LGI1-IgG. Less than 10% of 167 patients with neural autoantibodies other than VGKC-complex-IgG reported pain. CONCLUSIONS: Chronic idiopathic pain is a syndromic manifestation of VGKC-complex autoimmunity. Hyperexcitability of nociceptive pathways is implicated. CASPR2-IgG significantly associates with pain, but in most patients the antigenic VGKC-complex molecule remains to be determined. VGKC-complex autoimmunity represents an important new direction for pain research and therapy.
Assuntos
Autoanticorpos/imunologia , Doenças Autoimunes/complicações , Dor Crônica/etiologia , Canais de Potássio de Abertura Dependente da Tensão da Membrana/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Doenças Autoimunes/epidemiologia , Doenças Autoimunes/imunologia , Criança , Pré-Escolar , Dor Crônica/epidemiologia , Dor Crônica/imunologia , Feminino , Humanos , Imunoglobulina G/imunologia , Masculino , Pessoa de Meia-Idade , PrevalênciaRESUMO
OBJECTIVE: To identify the spectrum of sleep disorders associated with autoantibodies reactive with voltage-gated potassium channel (VGKC) complexes. DESIGN: Case series of all patients with neurologic disorders of VGKC autoimmunity evaluated in the Mayo Clinic Center for Sleep Medicine (Rochester, Minnesota) between January 1, 1994, and February 1, 2010. SETTING: Academic referral center. PATIENTS: Fifteen consecutive patients were identified with limbic encephalitis (n = 5), Morvan syndrome (n = 4), and overlapping features (n = 6). INTERVENTION: Ten patients received immunotherapy (corticosteroids, cyclophosphamide, or mycophenolate mofetil). MAIN OUTCOME MEASURE: Response to immunotherapy. RESULTS: The median VGKC autoantibody value at presentation was 1.51 nmol/L (range, 0.09-4.86 nmol/L). Neoplasms were discovered in 5 patients (33%) (thymoma [n = 2], prostate adenocarcinoma, colon adenocarcinoma, and melanoma). In 14 patients (93%), serious sleep disturbances were identified (insomnia, dream enactment behavior, suspected nocturnal epilepsy, and hypersomnia). Severe insomnia occurred in 9 patients (60%), regardless of neurologic presentation. Polysomnography at presentation (7 patients) revealed a mean sleep efficiency of 19% (4 patients had complete absence of sleep). Dream enactment behavior occurred in 8 patients (53%), including 3 of 5 with limbic encephalitis and all 4 with Morvan syndrome. Two of 7 polysomnograms demonstrated loss of rapid eye movement sleep muscle atonia; absent or minimal rapid eye movement sleep precluded interpretation in 4 patients. Sleep disorders resolved completely or almost completely in 8 of 10 patients who received immunotherapy. CONCLUSIONS: Sleep disorders are cardinal manifestations of VGKC complex autoimmunity in association with a spectrum of neurologic presentations. They may respond favorably to immunotherapy.
Assuntos
Doenças Autoimunes do Sistema Nervoso/complicações , Doenças Autoimunes do Sistema Nervoso/imunologia , Canais de Potássio de Abertura Dependente da Tensão da Membrana/imunologia , Transtornos do Sono-Vigília/diagnóstico , Transtornos do Sono-Vigília/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Autoanticorpos/biossíntese , Autoanticorpos/sangue , Doenças Autoimunes do Sistema Nervoso/tratamento farmacológico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
The authors describe the neuropsychiatric spectrum of voltage-gated potassium-channel complex (VGKC) autoimmunity among 67 seropositive patients; 2 had initially been assigned a primary psychiatric diagnosis. Diverse manifestations were recorded, often affective-predominant. Symptoms for 24 patients with florid presentations included confusion, 92%; memory impairment, 75%; personality change, 58%; depression, 33%; and anxiety, 29%. Of 15 who received immunotherapy, 67% improved. Forty-three patients with milder presentations or low positive VGKC complex Ab values are also described. Neuropsychiatric presentations were significantly associated with higher autoantibody values. Improvements were most evident in patients treated early, which emphasizes the need for early diagnosis and immunotherapy initiation.