Eventos en el centro germinal tras la estimulación con antígenos TIMO-DEPENDIENTES (proteicos)

Hipermutación somática

Maduración de la afinidad

Cambio de isotipo

• (“switch”)Generación de

células de memoria

Interacción entre linfocitos T y B

Tras la interacción del linf. B con el linf. T también se induce la expresión de AID (desaminasa de citidina Inducida por activación) yUNG (uracil-N-glicosilasa),enzimas que participan en:• Hipermutación somáticaY• Cambio de isotipo

NEMO: Escencial Modulator NF B

Diferencia entre recombinación e hipermutación

Cambio de isotipo

-AID first deaminates C to U, and then uracil-DNA glycosylase removes U, leaving an abasic site. Subsequent steps generate single-strand breaks [17], which become substrates for mutagenic repair or recombination. Somatic hypermutation alters variable region sequence, and switch recombination joins a new constant region (Cγ1) to the expressed variable region, producing an extrachromosomal DNA circle (bottom), which contains the deleted region. The final result is a heavy chain locus containing a mutated variable region (mutations are indicated by stars) and a chromosomal Sμ/Sγ1 junction (bottom).

--Somatic hypermutation is shown following switch recombination, but neither process is prerequisite for the other

Influencia de las citocinas en el cambio de isotipo ó clase de Ab.

Maduración de la afinidad(hipermutación y selección por las FDC)

Antes y después de formarse el centro germinal

Ulf Klein & Riccardo Dalla-FaveraNature Reviews Immunology 8, 22-33 (January 2008)

Centro germinal (¡good!)

Antigen-activated B cells differentiate into centroblasts that undergo clonal expansion in the dark zone of the germinal centre. During proliferation, the process of somatic hypermutation (SHM) introduces base-pair changes into the V(D)J region of the rearranged genes encoding the immunoglobulin variable region (IgV) of the heavy chain and light chain; some of these base-pair mutations lead to a change in the amino-acid sequence. Centroblasts then differentiate into centrocytes and move to the light zone, where the modified antigen receptor, with help from immune helper cells including T cells and follicular dendritic cells (FDCs), is selected for improved binding to the immunizing antigen. Newly generated centrocytes that produce an unfavourable antibody undergo apoptosis and are removed. A subset of centrocytes undergoes immunoglobulin class-switch recombination (CSR). Cycling of centroblasts and centrocytes between dark and light zones seems to be mediated by a chemokine gradient, presumably established by stromal cells in the respective zones (not shown)14. Antigen-selected centrocytes eventually differentiate into memory B cells or plasma cells.

Subpoblaciones de linfocitos TH

Figure 1.Functional development and activity of Th cell subpopulations. Activation of dendritic cells (DC) follows interaction of pattern recognition receptors such as C type lectin receptors (CLR) or toll like receptors (TLR) with molecules on the surface of microorganisms. Antigen presentation to naïve T cells results in the development of Th1, Th2 or Th17 cells depending on the cytokine milieu. Cells of the innate immune system, e.g. DC and NKT cells, are the source of promoting cytokines, IL-4, IL-6, TGF-β and IL-12. IL-23 promotes the expansion rather than the development of Th17 cells. The cytokines which are made would depend on the antigenic stimulus. The activity of Th cell subpopulations can be regulated by Tregs which may include naturally arising Foxp3-expressing Tregs.

Respuesta inmune y linfocitos TCD8

Tarea: ¿cómo se activa un linfocito TCD8?¿ cómo lleva a cabo su función ?

Cuestionario:

1. Esquema de la sinapsis inmunológica entre linfocito T y cel. Dendrítica

2. En qué consiste la selección positiva y la selección negativa para un linfocito T

3. A qué se debe la agammaglobulinemia de Bruton y cómo se puede diagnosticar

4. Qué enzima da lugar a la formación del DAG e IP3 y cómo actúan

5. Qué consecuencia hay por ausencia de la unión entre CD40-CD40L