Antibody Production and B Cells

• Antibody production and circulation relies on B cells.
• Plasma cells, differentiated B cells, secrete immunoglobulins (IG).
• Plasma cells lack detectable membrane-bound immunoglobulins.
• Plasma cells synthesize and secrete high levels of antibodies, up to 1000 IG molecules per cell per second.
• B cells can be activated by T-independent or T-dependent mechanisms.
• Cytokines facilitate B cell class switching when B cells receive a help signal from T cells.
• Class switching allows B cells to express or secrete different IG isotypes.
• Some activated B cells differentiate into plasma cells, while others become memory cells.

Germinal Centers

• Germinal centers are found in secondary lymphoid tissues like lymph nodes, spleen, and MALT.
• Germinal centers crucial for B cell activation, proliferation, and differentiation during adaptive immune response.
• Germinal centers form in response to antigen stimulation and are essential for generating high-affinity antibodies and memory B cells.
• Germinal centers are not in the thymus.
• B cells undergo rapid proliferation, differentiation, and selection within germinal centers.
• B cell activation and proliferation occur when B cells encounter their specific antigen in the presence of T helper cells, forming the germinal center.
• Somatic hypermutation introduces point mutations into immunoglobulin genes, resulting in slightly different antibodies.
• Affinity maturation selects B cells with the highest affinity for the antigen.
• Class switching allows B cells to change the type (isotype) of antibodies they produce (e.g., from IgM to IgG, IgA, or IgE), depending on cytokine signals.
• Some B cells differentiate into plasma cells, which produce and secrete large amounts of antibodies, while others become memory B cells.

Cytokines and B cell Differentiation

• B cell IG class switching and differentiation into plasma cells is directed by cytokines.
• Cytokine signals are needed for B cell differentiation.
• Proliferation and differentiation occurs in the light zone of thymus germinal centers.

Memory B Cells

• Memory B cells retain membrane-bound immunoglobulin, unlike plasma cells.
• Memory B cells differentiate similarly to plasma cells.
• Memory B cells maintain the membrane form of the heavy chain due to RNA processing as a consequence of class switching.
• Memory B cells express different isotypes.

Memory B Cells vs Naive B Cells

Plasma B Cells

• Typically, larger and more differentiated than naive or memory B cells.
• Abundant cytoplasm and well-developed endoplasmic reticulum.
• Express surface immunoglobulins (antibodies) identical to those on the naive B cell from which they differentiated.
• May express plasma cell markers such as CD138 (syndecan-1).
• Specialized for high-rate antibody production and secretion.
• Produce large quantities of antibodies with high specificity for the encountered antigen.
• Typically have a short lifespan, ranging from a few days to a few weeks.
• Exist primarily to produce antibodies in the immediate immune response.
• Primarily found in secondary lymphoid organs, bone marrow, and sites of infection or inflammation.
• Can secrete antibodies of various isotypes, including IgM, IgG, IgA, or IgE, depending on class-switching events.
• Do not undergo clonal expansion after activation and are Derived from the clonal expansion of activated B cells.

Memory B Cells

• Morphologically like naive B cells, smaller compared to plasma cells, with less cytoplasm.
• Express surface immunoglobulins specific to the encountered antigen.
• May express memory B cell markers such as CD27.
• Have a long lifespan, providing long-term immune memory and can persist for months to years.
• Primarily exist in a quiescent (non-dividing) state until reactivated by a subsequent encounter with the antigen.
• Upon re-exposure to the same antigen, memory B cells can rapidly differentiate into antibody-secreting plasma cells.
• Can secrete antibodies of various isotypes, like plasma cells and retain the ability to undergo class-switching upon reactivation.
• Circulate in the bloodstream and can migrate to peripheral tissues are also present in secondary lymphoid organs.
• Upon reactivation, undergo rapid clonal expansion to generate a larger pool of effector cells.

Somatic Hypermutation

• Restimulation of a memory B cell by its specific antigen can result in somatic hypermutation.
• Small point mutations accumulate in the DNA encoding variable regions of both light and heavy chains.
• Somatic hypermutation occurs in the germinal centers of secondary lymphoid organs
• Mutated B cells with improved antigen-binding affinity are preferentially selected for survival and proliferation.
• Affinity maturation results in the generation of antibodies with increased binding strength to their specific epitope
• B cells recognize individual antigens.
• B cells clone and form specialized cells called memory B cells and effector B cells after helper T cells deliver the co-stimulation needed for the B cell to proliferate and differentiate.
• Memory B cells are involved in a secondary immune response; if the same antigen enters the body again in the future, 1000s of memory cells are available to initiate a quick reaction, destroying the antigen before any signs or symptoms can occur and can last for decades
• Effector B cells, called plasma cells, secrete millions of antibodies which have the same antigen-combining properties as the receptor molecules on the surface of the original B cell; the antibodies will only combine with the antigen that originally activated them.

Primary vs Secondary Immune Response

• The difference between antibodies secreted by plasma cells during first exposure (primary immune response) and subsequent exposures (secondary immune response) lies in their class, affinity, quantity, and speed of production:
• Plasma cells primarily secrete IgM, the first antibody produced by B cells, which is effective in initial pathogen clearance but has relatively low affinity.
• Plasma cells predominantly produce IgG (or IgA/IgE, depending on the pathogen and tissue type). These antibodies are more specialized and efficient at neutralization, opsonization, and complement activation.

Antibody Affinity

• Antibodies have low to moderate affinity at the start of the response because they are produced by naive B cells that have not undergone significant refinement.
• Memory B cells, which have already undergone affinity maturation, are reactivated and rapidly produce high-affinity antibodies, more effective at neutralizing pathogens and initiating immune responses.

Quantity of Antibody

• The quantity of antibodies is relatively low and increases gradually over days to weeks as the immune response develops.
• The quantity of antibodies is significantly higher and produced much faster due to the activation of memory B cells, which are primed to respond.

Production Speed of Antibody

• It takes several days for naive B cells to become activated, differentiate into plasma cells, and start secreting antibodies and the immune response may lag behind the pathogen's replication.
• Memory B cells respond immediately, leading to a rapid surge in antibody production, often neutralizing the pathogen before it causes significant harm.

Plasma Cells

• Arise from naive B cells activated upon first exposure to a pathogen and produce antibodies for immediate, short-term defense.
• Memory B cells arise from naive B cells after they have undergone affinity maturation and differentiation during the primary response and rapidly re-activate and produce antibodies upon subsequent exposure to the same pathogen.

Quantity of antibodies

• Plasma cells produce antibodies gradually during the first immune response, peaking after days to weeks.
• Memory B cells produce large quantities of antibodies quickly upon re-exposure, resulting in a more robust response.

Speed of production

• Plasma cells have slow activation (several days to weeks to reach peak production).
• Memory B Cells have rapid activation (hours to days) due to prior sensitization.

Lifespan of effect

• Plasma Cells have a short-lived effect, providing immediate, temporary immunity during the active phase of infection.
• Memory B cells are long-lived and ready to mount faster, stronger responses during future exposures.

Overall

• Plasma cells are responsible for producing antibodies during the primary immune response; these antibodies are less refined, predominantly IgM, and gradually shift to other isotypes as the response progresses and provide the first line of defense against an unfamiliar pathogen.
• Memory B cells produce high-affinity antibodies during secondary immune responses, these antibodies are predominantly IgG (or IgA/E in specific contexts), and their production is faster, more abundant, and highly specific to the previously encountered antigen which is the basis for long-term immunity and why vaccination works effectively.