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Complement System01:27

Complement System

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The complement system is a group of approximately 20 plasma proteins that strengthen the body's defenses against infections through opsonization, inflammation, and cell lysis. Opsonization involves coating pathogens with complement proteins, making them more recognizable and facilitating phagocyte engulfment. Certain complement proteins induce inflammation that attracts immune cells to the site of infection. Cell lysis involves the destruction of pathogens through the formation of a...
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Caspase, a family of cysteine proteases, serve as effectors in apoptosis. The ced3 gene in C.elegans was first identified to be involved in apoptosis. This gene encodes the ced-3 caspase that is similar to the interleukin-1-beta converting enzyme or ICE in mammals. In addition to apoptosis, caspases also function in the inflammatory response. Inflammatory caspases are essential in activating pro-inflammatory cytokines that recruit immune cells and block the replication of pathogens inside...
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The Extrinsic Apoptotic Pathway01:17

The Extrinsic Apoptotic Pathway

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The extrinsic apoptotic pathway is initiated when extracellular death-inducing signals, such as specific cytokines, activate the death receptors expressed on the cell surface. The immune cells involved in this pathway are natural killer cells (NK cells) and cytotoxic T-lymphocytes. NK cells are critical in innate immune response, while cytotoxic T-lymphocytes are associated with adaptive immune response. These cells recognize specific receptors expressed on the altered cells and activate...
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The Intrinsic Apoptotic Pathway01:31

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Internal cellular stress, such as cellular injury or hypoxia, triggers intrinsic apoptosis. The B-cell lymphoma 2 (Bcl-2) family of proteins are the primary regulators of the intrinsic apoptotic pathway. For example, during DNA damage, checkpoint proteins, such as Ataxia Telangiectasia Mutated (ATM protein) and Checkpoints Factor-2 (Chk2) proteins, are activated. These proteins phosphorylate p53 which further activates pro-apoptotic proteins, such as Bax, Bak, PUMA, and Noxa, and inhibits...
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Cytotoxic T Cells-mediated Immune Response01:27

Cytotoxic T Cells-mediated Immune Response

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Cytotoxic T cells are a vital component of the immune system. They have the remarkable ability to identify and target antigens on infected or abnormal cells. These antigens often originate from intracellular pathogens such as viruses or abnormal proteins cancer cells produce.
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Role of Matrix Metalloproteases in Degradation of ECM01:23

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Matrix metalloproteases (MMPs) are enzymes involved in the hydrolysis of proteins and glycoproteins of the extracellular matrix. MMPs are essential for the migration and proliferation of cells through the dense matrix network, throughout embryonic development, and throughout morphogenesis. The first MMP activity discovered was a collagenase in a tadpole's tail undergoing metamorphosis. The active collagen deposition and modifications lead to the morphogenesis of tadpoles into the adult...
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Updated: May 29, 2025

A Colorimetric Assay that Specifically Measures Granzyme B Proteolytic Activity: Hydrolysis of Boc-Ala-Ala-Asp-S-Bzl
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Granzyme K activa toda la cascada del complemento

Carlos A Donado1, Erin Theisen1,2, Fan Zhang3

  • 1Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.

Nature
|February 6, 2025
PubMed
Resumen
Este resumen es generado por máquina.

Granzyme K (GZMK), una enzima derivada de los linfocitos, activa la cascada del complemento, impulsando la inflamación en enfermedades como la artritis reumatoide. Los ratones que carecen de GZMK muestran una reducción de la enfermedad inflamatoria, destacando GZMK

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Área de la Ciencia:

  • Inmunología
  • Función de la proteasa
  • Biología del sistema de complemento

Sus antecedentes:

  • Las granzimas son proteasas de serina principalmente de los linfocitos citotóxicos.
  • Su papel en la muerte celular está establecido, pero las funciones extracelulares, incluida la inflamación, están surgiendo.
  • Granzyme K (GZMK) es abundante en las células T CD8 + en la artritis reumatoide sinovial, pero su función no está clara.

Objetivo del estudio:

  • Para aclarar la función de Granzyme K (GZMK).
  • Para investigar el papel de GZMK en la activación de la cascada del complemento.
  • Para determinar la contribución de GZMK a las enfermedades inflamatorias.

Principales métodos:

  • Ensayos bioquímicos para evaluar la escisión de las proteínas del complemento C2 y C4 por GZMK.
  • Análisis de las vías de activación del complemento in vitro.
  • Estudios in vivo con ratones con deficiencia de Gzmk para evaluar los fenotipos de las enfermedades inflamatorias.
  • El análisis inmunohistoquímico de la artritis reumatoide sinovial.

Principales resultados:

  • GZMK divide directamente las proteínas del complemento C4 y C2, iniciando la cascada del complemento.
  • La activación mediada por GZMK genera todas las moléculas efectoras del complemento, incluidas las anafilatoxinas y el complejo de ataque de membrana.
  • GZMK está localizado en las áreas de activación del complemento en la artritis reumatoide sinovial.
  • Los ratones con deficiencia de Gzmk presentan una reducción significativa de la artritis y la dermatitis, con una disminución de la activación del complemento.

Conclusiones:

  • GZMK es un nuevo activador de la cascada clásica del complemento.
  • El GZMK derivado de linfocitos impulsa la inflamación mediada por el complemento en enfermedades inflamatorias crónicas.
  • Dirigirse a GZMK puede ofrecer una estrategia terapéutica para las afecciones inflamatorias.