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Previous issue date: 2015-03-17 / Indrodu??o. A S?ndrome de Guillain-Barr? (SGB) ? uma polineuropatia imunomediada,
sendo, atualmente, a mais frequente causa de paralisia aguda
neuromuscular. As principais variantes dessa s?ndrome s?o: a polineuropatia
desmielinizante inflamat?ria aguda (PDIA), a neuropatia axonal motora aguda
(NAMA), a neuropatia axonal motora e sensitiva aguda (NAMSA), e a s?ndrome de
Miller-Fisher. H? tamb?m diferen?as na distribui??o geogr?fica destas variantes. A
resposta imune aberrante, p?s infec??o, parece ser resultante de um mimetismo
molecular, devido a forma??o de autoanticorpos e ativa??o do sistema
complemento e de citocinas. S?o encontrados polimorfismos bial?licos nos genes
codificadores dos receptores das fra??es Fc das imunoglobulinas (FcRIIa, FcRIIIa
e FcRIIIb) que afetam a afinidade e efici?ncia na resposta imune celular, sugerindo
a exist?ncia de susceptibilidade individual no risco de desenvolver a SGB. No
Brasil, h? poucos estudos epidemiol?gicos sobre a SGB e nenhum relato sobre a
frequ?ncia das variantes e suas manifesta??es cl?nicas. Os objetivos deste estudo
foram: (1) caracterizar a SGB e suas manifesta??es cl?nicas em uma coorte de
pacientes com SGB oriundos do Estado do Rio Grande do Norte (RN); (2)
determinar se polimorfismos em receptores FcR est?o envolvidos com o risco de
doen?a, e (3) avaliar a express?o g?nica global buscando identificar poss?veis vias
que poderiam ser moduladas na fase inicial da doen?a e, consequentemente,
diminuir o tempo de doen?a.
Metodologia. Foram recrutados 149 casos de SGB diagnosticados entre 1994-
2013 no RN, tendo sido avaliados os dados cl?nicos e laboratoriais visando a
determinar a evolu??o. DNA e RNA foram extra?dos do sangue perif?rico e
anticorpos antiganglios?deos foram determinados em amostras de soro. Foram
genotipados polimorfismos nos genes FCGR2A e FCGR3A, em pessoas com SGB
(n=141) e controles saud?veis (n=364), sendo ainda analisadas as express?es
g?nicas globais de 12 pacientes com SGB, por RNAseq. As amostras de sangue
para os estudos de express?o g?nica foram coletadas ao diagn?stico e p?srecupera??o.
Resultados. A incid?ncia de SGB foi de 0,3/100 mil pessoas no RN, sem presen?a
de sazonalidade, com os casos ocorrendo em uma idade mais jovem. A SGB foi precedida por infec??es em 63,7%, sendo a diarreia associada a variante axonal
(p=0,025). A PDIA foi a variante mais frequente (81,8%), seguida de NAMA
(14,7%) e de NAMSA (3,3%). A distribui??o da fraqueza muscular correlacionou
com as variantes, sendo a proximal mais frequente na PDIA, enquanto a distal
predominou na variante axonal. O nadir < 10 dias ocorreu em 84,6% dos indiv?duos
na variante axonal e 42,4% dos casos com PDIA (P<0,0001). A forma
desmielinizante apresentou uma recupera??o na deambula??o mais r?pida do que
a variante axonal (P<0,0001). A mortalidade de SGB foi de 5,3%. O pior
progn?stico aos 12 meses estava associado com a variante axonal (OR 17,063; P
= 0,03) e no tempo de melhora um ponto na escala funcional de Hughes (OR
1,028; P = 0.03). As distribui??es dos gen?tipos e alelos em FCGR2A (p=0,367) e
em FCGR3A (p=0,2430) n?o foram diferentes entre os pacientes com SGB e
controles. A an?lise da express?o g?nica global mostrou varia??o na express?o
dos mRNAs de isoformas de prote?nas associadas ? fase sintom?tica da doen?a.
Conclus?es. N?o h? sazonalidade na ocorr?ncia da SGB no RN, havendo um
predom?nio da variante desmielinizante e 50% dos casos tinham idade inferior a 20
anos. A variante axonal est? associada ao mau progn?stico. O diagn?stico precoce
e a identifica??o da variante, acompanhada de interven??es adequadas, levam a
diminui??o da morbidade a longo prazo. Varia??es polim?rficas nos genes de
FCGR parecem n?o influenciar a susceptibilidade ou o curso da SGB nessa
popula??o. Varia??es na express?o g?nica apontam para vias de desregula??o e
altera??es em intera??es transcricionais, que podem ser utilizadas como potenciais
alvos de modula??o. / Introduction. Guillain-Barr? syndrome (GBS) is an immune-mediated
polyneuropathy and the principal cause of acute neuromuscular paralysis. The most
prominent GBS subtypes are: acute inflammatory demyelinating polyneuropathy
(AIDP), acute motor axonal neuropathy (AMAN), acute motor-sensory axonal
neuropathy (AMSAN) and Fisher syndrome (FS). Differences in geographical
distribution of variants have been reported. In Brazil, there are few studies
describing the characteristics of GBS, but none on the frequency of GBS variants
and their clinical manifestations. Infection-induced aberrant immune response
resulting from molecular mimicry and formation of cross-reacting antibodies,
contribute to complement activation. Functional biallelic polymorphism in
immunoglobulin receptors that influence the affinity of IgG subclasses and the type
of immune response have been described, suggesting genetic susceptibility to
developing disease. It remains unclear whether individuals carrying different FCGR
alleles have differential risk for GBS and?or disease severity. The goals of this study
were: (1) To characterize GBS and describe the clinical findings in a cohort of
patients with GBS from the state of Rio Grande do Norte, Brazil; (2) to determine
whether polymorphism in FCGR were associated with development of GBS, and (3)
to tease out whether the global gene expression studies could be a tool to identify
pathways and transcriptional networks which could be regulated and decrease the
time of disease.
Methods. Clinical and laboratory data for 149 cases of GBS diagnosed from 1994
to 2013 were analyzed. Genomic DNA and total RNA were extracted from whole
blood. Antigangliosides antibodies were determined in the sera. In addition, we
also assessed whether FCGR polymorphism are present in GBS (n=141) and blood
donors (n=364), and global gene expressions were determined for 12 participants
with GBS. Blood samples were collected at the diagnosis and post-recovery.
Results. AIDP was the most frequent variant (81.8%) of GBS, followed by AMAN
(14.7%) and AMSAN (3.3%). The incidence of GBS was 0.3 ? 100,000 people for
the state of Rio Grande do Norte and cases occurred at a younger age. GBS was
preceded by infections, with the axonal variant associated with episodes of diarrhea
(P = 0.025). Proximal weakness was more frequent in AIDP, and distal weakness predominant in the axonal variant. Compared to 42.4% of cases with AIDP
(P<0.0001), 84.6% of cases with the axonal variant had nadir in <10 days.
Individuals with the axonal variant took longer to recover deambulation (P<0.0001).
The mortality of GBS was 5.3%. A worse outcome was related to an axonal variant
(OR17.063; P=0.03) and time required to improve one point in the Hughes
functional scale (OR 1.028; P=0.03). The FCGR genotypes and allele frequencies
did not differ significantly between the patients with GBS and the controls (FCGR2A
p=0.367 and FCGR3A p=0.2430). Global gene expression using RNAseq showed
variation in transcript coding for protein isoforms during acute phase of disease.
Conclusions. The annual incidence of GBS was 0.3 per 100,00 and there was no
seasonal pattern. A predominance of the AIDP variant was seen, and the incidence
of the disease decreased with age. The distribution of weakness is a function of the
clinical variants, and individuals with the axonal variant had a poorer prognosis.
Early diagnosis and variant identification leads to proper intervention decreasing in
long-term morbidity. FCGR polymorphisms do not seem to influence susceptibility to
GBS in this population. This study found deregulated genes and signs of
transcriptional network alterations during the acute and recovery phases in GBS.
Identification of pathways altered during disease might be target for immune
regulation and with potential to ameliorate symptoms.
| Identifer | oai:union.ndltd.org:IBICT/oai:repositorio.ufrn.br:123456789/20220 |
| Date | 17 March 2015 |
| Creators | Dourado J?nior, M?rio Em?lio Teixeira |
| Contributors | 15603016434, http://lattes.cnpq.br/7120263570947836, Oliveira, Acary Souza Bulle de, 05056558885, Lima, Jo?o Paulo Matos Santos, 79332021368, http://lattes.cnpq.br/3289758851760692, Costa, Marcos Romualdo, 05278916737, http://lattes.cnpq.br/6118493598074445, Nascimento, Osvaldo Jos? Moreira, 26313782704, Jer?nimo, Selma Maria Bezerra |
| Publisher | Universidade Federal do Rio Grande do Norte, PROGRAMA DE P?S-GRADUA??O EM CI?NCIAS DA SA?DE, UFRN, Brasil |
| Source Sets | IBICT Brazilian ETDs |
| Language | Portuguese |
| Detected Language | English |
| Type | info:eu-repo/semantics/publishedVersion, info:eu-repo/semantics/doctoralThesis |
| Source | reponame:Repositório Institucional da UFRN, instname:Universidade Federal do Rio Grande do Norte, instacron:UFRN |
| Rights | info:eu-repo/semantics/openAccess |
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