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Master's Dissertation
DOI
10.11606/D.42.2007.tde-05102007-153124
Document
Author
Full name
Juliana Sayuri Kuribayashi
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2007
Supervisor
Committee
Camargo, Maristela Martins de (President)
Barbuto, Jose Alexandre Marzagao
Fonseca, Simone Gonçalves da
Title in Portuguese
A desregulação da via UPR associada à imunodeficiência comum variável.
Keywords in Portuguese
Imunoglobulinas
Imunologia
Linfócitos B
RetículImunodeficiência comum variávelo endoplasmático
Via UPR.
Abstract in Portuguese
A imunodeficiência comum variável (CVID) é caracterizada por hipogamaglobulinemia e infecções recidivantes. Neste estudo verificamos o papel da via Unfolded Protein Response (UPR) na patogênese da doença. Uma paciente com CVID apresentou expressão aumentada do RNAm XBP-1 unspliced e co-localização de IgM e BiP no retículo endoplasmático (RE). Verificamos a ausência de mutações nos produtos obtidos por RT-PCR de XBP-1 e nos domínios quinase/endonuclease da IRE-1a. Análises por Q-PCR dos RNAm XBP-1 spliced, IRE-1a e BiP após tratamento com LPS ou brefeldina A mostrou que, ao contrário dos controles saudáveis que respondem a estes estressores com ondas de transcrição destes três genes, esta paciente apresenta baixos níveis de transcrição, não atingindo o mesmo nível de resposta apresentado pelos indivíduos saudáveis. Nossos achados associam o splicing diminuído do RNAm XBP-1 ao acúmulo de IgM no RE e baixas taxas de transcrição de chaperonas, fornecendo um mecanismo para explicar a hipogamaglobulinemia observada em uma paciente com CVID.
Title in English
Dysregulation of unfolded protein response associated with common variable immunodeficiency.
Keywords in English
B Cells
Common variable immunodeficiency
Endoplasmic reticulum
immunoglobulins.
Immunology
Unfolded Portein response pathway
Abstract in English
Common Variable Immunodeficiency (CVID) is characterized by hypogammaglobulinemia and recurrent infections. Herein we addressed the role of Unfolded Protein Response (UPR) in the pathogenesis of the disease. Augmented unspliced XBP-1 mRNA concurrent with co-localization of IgM and BiP was found in one CVID patient. Sequencing of RT-PCR amplicons did not reveal any mutation on XBP-1 neither on the kinase/endonuclease domains of IRE-1a. Q-PCR analysis of spliced XBP-1, IRE-1a and BiP after LPS or Brefeldin A treatment showed that, unlike healthy controls that respond to these ER stressors by presenting waves of transcription of these three genes, the cells presented lower rates of transcription, not reaching the same level of response of healthy subjects. Our findings associate diminished splicing of XBP-1 mRNA with accumulation of IgM within the ER and lower rates of chaperone transcription, therefore providing a mechanism to explain the observed hypogammaglobulinemia.
 
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TDE_2007_02.pdf (1.27 Mbytes)
Publishing Date
2007-10-17
 
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