B-cel

Lymfocyten: B-lymfocyten, T-lymfocyten en NK-cellen

HSCs first give rise to multipotent progenitors (MPPs), a subset of which retain the capacity to produce either myeloid or lymphoid cells. In the bone marrow, the progeny of some of these "lymphoid-competent" MPPs become committed to the B cell lineage, an event that requires the transcription factors EBF1 and Pax5 and the suppression of Notch signaling, which otherwise overrides B cell differentiation programs and directs MPPs towards the T cell lineage. Other early progenitors in marrow (sometimes known as early thymic progenitors, or ETPs) migrate to the thymus, an organ rich in stromal cells expressing ligands that activate Notch signaling, which induces these cells to undergo T cell differentiation.

Lymfeklier

blauw; cortex (B-cel zone met follikels en kiemcentra), geel; paracortex (T-cel zone)

Lymfoïde weefsel

  • primair: beenmerg (B cel) en thymus (T cel)

  • secundair: lymfeklieren, milt en mucosa-geassocieerd lymfoïd weefsel (MALT)

MALT is een verzameling lymfefollikels die zijn gelegen in de mucosa van de tractus digestivus, meer bepaald in de tonsillen, Peyerse platen en de appendix. Anders dan bij de lymfeknopen zijn deze structuren niet omgeven door een kapsel en zijn ze ook niet verbonden met lymfevaten. Hun interne structuur is eenvoudig in vergelijking met lymfeknopen.

Lymfeklier

The lymph nodes are organized lymphoid organs that contain lymphocytes within a fine reticular stroma. The structures within a lymph node include the capsule, subcapsular sinus, cortex (B cell zone with follicles and germinal centers), paracortex (T cell zone), medullary sinuses, medullary cords and hilus.

Germinal center (kiemcentra)

The germinal center (GC) is a specialized microstructure that forms in secondary lymphoid tissues, producing long-lived antibody secreting plasma cells and memory B cells, which can provide protection against reinfection. Within the GC, B cells undergo somatic mutation of the genes encoding their B cell receptors which, following successful selection, can lead to the emergence of B cell clones that bind antigen with high affinity.

  • Germinal centre:

    • dark zone: centroblast

    • light zone: centrocyt

  • Mantle zone

  • Marginal zone

B-cellen

B-cell neoplasms tend to mimic various stages of normal B cell differentiation and this resemblance to normal cell stages is a major basis for their classification and nomenclature.

B-cel ontwikkeling

In beenmerg:

  • B progenitor cel (synoniem: pre-pro-B of B-lymfoblast) --> pro-B cel --> pre-B cel --> immature B cel

Secundaire lymfoïde organen:

  • mature/naïeve B-cel -> antigen-activated B cel;

    • short-lived plasmacel, OF

    • extrafolliculaire blast --> centroblast --> centrocyte;

      • Long-lived plasmacel, OF

      • Memory B cel


Antigen independent

Pro-B cel

Markers:

  • Geen BCR (B-cel receptor)

Pre-B cel

Markers:

  • Pre-BCR (IgH genes complete VDJ gene rearrangement, allowing the surface expression of a complex consisting of an Ig heavy chain and molecules called surrogate light chains that show homology to Ig light chain V and C regions)

Immature B cel

Markers:

  • Immature BCR (successful rearrangement of either a kappa or lambda Ig light chain gene (expression of IgM). If surface IgM interacts strongly with membrane-bound self-antigen (such as MHC) on other cells, then that B cell either dies by apoptosis or undergoes further Ig gene rearrangement (=receptor editing) to create a new Ig with a different specificity)

Antigen dependent

Mature/naïeve B cel

Markers:

  • Mature BCR: IgM en IgD (surface Ig; sIg)

Germinal center B-cel

Upon encountering antigen that fits their surface Ig receptors, naïve B-cells undergo transformation and form either short-lived plasmacells or migrate into the centre of a primary follicle, proliferate and fill the FDC meshwork; forming a germinal centre.

Germinal centre centroblasts express low levels of sIg and also switch off expression of BCL2protein (thus, susceptable for apoptosis). Centroblasts express CD10 and BCL6 protein.

In the GC somatic hypermutation occurs in the Ig heavy and light chain variable region genes. Also, some cells switch in class (from IgM to IgG or IgA). The BCL6 gene also undergoes somatic mutation (at a lower frequency than Ig genes).

Centroblasts maure into centrocytes (or undergo apoptosis). Centrocytes with mutations that result in increased affinity are rescued from apoptosis and they re-express BCL2. Centrocytes switch of BCL6 and differentiate in plasmacells or memory B-cells.

Plasmacellen

The plasma cell is large and secretes antibodies, although it has few antibody molecules on its surface. Plasma cells that arise from follicular B cells are found mainly in the bone marrow and are long-lived (months to years), whereas plasma cells arising from non-follicular B cells have life spans of only days to a few weeks.

Markers:

  • CD38, CD138, appearance of XBP-1, BLIMP-1, PRDIBF1 en cytoplasmic Ig (cIg)

Memory B-cellen (marginale zone)

The memory B cell is identical in appearance to resting mature B cells. The life span of the memory cell is not precisely known, but they may persist for years, if not decades. Recall that mature naïve B cells express surface IgM and IgD. After activation, B cells no longer express IgD. If a memory B cell underwent class-switching in a germinal center it will express either IgG, or IgA, or IgE on the surface. If not, it retains expression of IgM and IgD ("unswitched"). Memory B cells also express CD27 . This interaction modulates memory B cell activation.

Using these markers, one may distinguish several subsets of B cells:

  • Mature naïve B cells – IgM+IgD+CD27-

  • Unswitched memory B cells – IgM+IgD+CD27+

  • Switched memory B cells – IgM-IgD-CD27+

Immuunglobulines

Structuur

  • 2 identieke heavy (H) chains - zware ketens

    • variable (V) region + three constant (C) regions

    • Type: gamma, alpha, mu, epsilon en delta

  • 2 identieke light (L) chains - lichte ketens

    • variable (V) region + constant (C) region

    • Type: kappa of lambda

The variable region determines antigen specificity, while the constant region is important in binding to Fc receptors and complement components.

Vormen immuunglobulines

  • Secreted — Secreted immunoglobulin is made mainly by plasma cells and may bind to microbes and act to neutralize, opsonize, fix complement, or serve other functions.

  • Membrane-bound — Membrane-bound immunoglobulin, in association with signal transducing molecules, Igalpha and Igbeta, serves as a receptor for antigen on the surface of B cells (BCR). The role of the BCR is to recognize, bind, and present antigen specific for the variable region. This also creates a tonic signal for B cell survival during B cell development.


Immunoglobuline rearrangements

The germline DNA contains segments coding for different portions of the immunoglobulin molecule:

  • Heavy chain (VDJ): very large number of variable (V) segments, a smaller number of diversity (D) segments, a few joining (J) segments, and a constant region for each subclass of immunoglobulin heavy chains (mu, gamma, alpha, delta, and epsilon).

  • Light chain: similar organization, but lack D segments.

Zware keten - herschikking

The Ig heavy chain locus is on chromosome 14

Lichte keten - herschikking