B cells and antibodies

B cells

White blood cell called lymphocytes that make infection-fighting proteins called antibodies.

• B cells make antibodies in response to antigens (antibody generators).

• Originally discovered in the Bursa of Fabricus in birds (hence the B in B cells)

B cells location

In foetuses, the liver makes B cells.

- Once you're born, B cells develop in the spongy tissue inside your bone called bone marrow.

-They start as hematopoietic stem cells and eventually become B cells during a process called hematopoiesis.

- Once they're fully mature, your B cells travel to important parts of your lymphatic system, including your spleen and lymph nodes.

B cells as professional APCs

• B cells express both major histocompatibility complex (MHC) I and MHC II

• are equipped with all the machinery required for antigen uptake, processing, and presentation.

-Hence, they are also classified as professional APCs, like dendritic cells (DC), monocytes and macrophages

B cell activation

B cells absorb the antigen and then present pieces of the antigen on their surface via a major histocompatibility complex (MHC). (Will be a exam question on this)

• Helper T cells-particualry Th2. can then recognise those antigens via the MHC and activate the B cells.

• Activated B cells can then either become effector B cellsor memory B cells.

• Effector B cells, also called plasma cells, produce antibodies. Antibodies work as tags or alarms to target invading agents for destruction by other immune agents like macrophages.

• Memory B cells, like memory T cells, help the immune system respond more quickly to future invasions by the same agent.

Different subtypes of CD4+cells

-Th1 Cells

-Th2 Cells

-Th17 Cell

-Treg Cells

Th2 helper cells lead to a..

Humoral immune response

Humoral (B-cells/Ab) vs cell-mediated (T cells)

• B cells activate humoral immunity, whereas T cells activate cell-mediated immunity.

• Humoral immunity produces antigen-specific antibodies, whereas cell-mediated immunity does not.

• Extracellular microorganisms and their poisons are targeted by humoral immunity

.• Intracellular microorganisms (such as bacteria) and tumor cells are targets of cell-mediated immunity.

• Humoral immunity recognises the unprocessed antigens.

• Cytokines are released by T-cells.

• Tumor cells and transplants are immune to humoral immunity.

• Tumor cells and transplants are both affected by cell-mediated immunity because they're recognised as intracellular

Receptors of adaptive immunity

Structures of both T and B cell receptors are defined by 3 regions:

-the variable constant -transmembrane regions.

-Precise T cell and B cell structure is important for activation.

-In both BCRs and TCRs it is the variable region that constitutes the antigen-bindingsite.

-B cell receptor (BCR) also defines the antigen specificity of the cell.

Differences between T cells and Bcells

T cells mature in thymus wheras B cells mature in bone marrow

-Receptor:

-TCR-cell surface receptor for T Cells,

-BCR-membrane Ig for B cells

Recognition:

-T cells recognise processed antigen

-B cells recognises native antigen (hydrophilic amino acids-soluble antigens, e.g. protein,polysaccharide, lipid)

The 2 types of B cells

-Plasma cells

-Memory cells

Plasma cells features

• Plasma cells release antibodies in response to antigens.

• Once a B cell becomes a mature plasma cell, it can release up to 2,000 antibodies per second.

• Plasma cells are also called plasmacytes or effector cells.

Memory Cells features

• Memory cells remember particular antigens, so if they appear in your body in the future, yourimmune system can mount a defence quickly.

• While plasma cells fight bodily invaders by producing antibodies, memory cells help your immune system fight in the future.

• For example, most vaccines work because they expose your immune system to antigens that your memory cells remember. If an invader appears, your body can mount an attack quickly.

Multiple myeloma - abnormalplasma cells

Multiple myeloma cells are abnormal plasma cells that build up in the bone marrow and form tumours in many bones of the body.

• As the number of multiple myeloma cells increases, more antibodies are made.

• This can cause the blood to thickena nd keep the bone marrow from making enough healthy blood cells.

• Multiple myeloma cells also damage and weaken the bone

Memory cells

• Lymphocytes are produced in response to the specific antigens on a pathogen.

• After the pathogen is removed some of the lymphocytes continue to remain in theimmune system.

• These are called memory cells.

• If the same pathogen enters the immune system for a second time, the response is much more rapid.

• This is because the existing memory cells are able to multiply rapidly, producing clones of the specific lymphocyte required to attack and destroy the pathogen before the individual exhibits symptoms

Primary Immune response

Memory B-cells are long-lived plasma cells that are formed mainly in the germinal centres.

• During the primary immune response, naïve B-cells are activated by T-cells. After that, B-cells move to secondary lymphoid organs like the spleen and lymph nodes where they enter B-cell follicles or germinal centres within the cortex.

• Inside the germinal centre, B-cells proliferate and undergo somatic hypermutation, which changes the affinity of their receptor.

- The receptors are then tested for their affinity within the germinal centre.

-In summary, B-cells that can bind their antigens on follicular dendritic cells subsequently receive survival signals from T-cells, while those that do not bind or bind with less affinity are outcompeted and undergo apoptosis.

- Moreover, B-cells will class switch from IgM to other antibody types such as IgA or IgG.

-After somatic hypermutation and class-switching, B-cells differentiate into plasma cells and memory B-cells.Plasma cells are short-lived and die quickly following the primary immune response.

Secondary Immune Response

• When these memory cells meet their specific antigen again, they rapidly proliferate and differentiate intoplasma cells.

These plasma cells then respond by producing abundant quantities of antibody to clear the antigen.

• A subset of these memory cells can also go into the germinal centres for further class switching and affinity maturation.

• Memory B-cells can also activate effector T-cells by presenting antigen on MHC-II molecules.

• The process of differentiation from memory B-cell to plasma cell is quicker than if they have differentiated from naïve B cells.

-Memory cells can survive for decades and so can respond to multiple exposures over time.

• Furthermore, they do not require continual interaction with antigen or T-cells to survive.

• As they have already undergone class switching and affinity maturation, they can divide faster and produce higher affinity antibodies such as IgG in response t antigen

Antibodies or Immunoglobulins overview

-Antibodies are naturally produced by plasma cells within the human body to mediate an adaptive immune responseagainst invading pathogens.

An antibody molecule consists of:

2 heavy chains (50 kDa each)

2 light chains (25 kDa each

Antibodies/immunoglobulin charachteristics

• These chains are interconnected by disulfide bonds, resulting in acharacteristic Y-shaped structure with a total molecular weightof approximately 150 kDa.

• Each antibody molecule possesses distinct variable and constant regions.

• The variable region confers an antibody's antigen-bindingspecificity.

-This region contains two fragment antigen binding(Fab) domains, each capable of binding a specific epitope (thepart of an antigen recognised by an antibody).

5 types of antibodies

There are five main types (isotypes) of antibodies, each with distinct structures and functions:IgG, IgM, IgA, IgE, and IgD.

IgG

• IgG is the most abundant Ig in human serum (70-75% of the total Ig in the blood).

• IgG promotes phagocytosis by initiating opsonisation, a process whereby pathogens (e.g., bacteria) are coated with antibodies, thereby enhancing their recognition and subsequent engulfment by phagocytes

IgG is the only immunoglobulin capable of placental transfer, conferring passiveimmunity to the developing fetus and neonates for the first few months after birth

.• Active immunity can be induced through vaccination.• Provides long-term immunity

.• IgG is critical for secondary immune responses e.g. anti-D duringpregnancy

IgM

Early response and complement activationIgM is the largest antibody isotype and the first to be secreted during a primary immune response to an antigen or microbe -> Primary immune response.

Representing approximately 5% of serum immunoglobulins, IgM is typically found as a pentamer composed offive identical subunits connected by disulfide bonds and a J chain.

-In addition, IgM also exists as secretory IgM, which is synthesised by plasma cells in mucosal-associated lymphoid tissue (MALT) and other glandular tissues.

Because of its large size and polymeric structure, IgM is largely confined to the intravascular space and exhibits a lower binding affinity for individual epitopes compared to IgG.

-Despite this lower affinity, the pentameric form of IgM possesses tenantigen-binding sites, resulting in high avidity (overall binding strength).

-This highavidity makes IgM a highly efficient activator of the classical complement pathway anda potent inducer of agglutination (to be studied in 3rd year).A monomeric form of IgM is expressed on the surface of B cells, enabling recognitionand B-cell activation.

IgE

Allergies and defence against parasites via mast cell activation

• In response to pathogens, IgE antibodies bound to mast cells through high-affinity receptors undergo cross-linking upon antigen binding.

- This cross-linking triggers mast cell degranulation, releasing inflammatory mediators that recruit eosinophils to the site of infection

IgD

Present on immature B-cells;function is not well understood

• IgD is primarily known for its role as a B-cell antigen receptor (BCR) on the surface of B cells.

• The precise mechanisms and full extent of IgD's functions are still under investigation.

• Still, current evidence suggests a role in regulating B-cell selection and maintaining B-cell homeostasis, thus influencing humoral immune responses.

• Recently, it has also been suggested that IgD signalling can be a novel therapeutic target for treating Tcell-related diseases, such as autoimmune and haematological diseases.

IgA

Mucosal protection and neonataldefence

• IgA represents 10-15% of the total immunoglobulins in serum

• is found in various secretions, including nasal mucus, saliva, breast milk, and intestinal fluid.

• IgA plays a crucial role in mucosal immunity, providing the first line of defence against pathogens encountered at mucosal surfaces, such as those of the respiratory and gastrointestinal tracts.

• The importance of IgA in maintaining mucosal immunity is highlighted by the increased susceptibility to infections observed in individuals with IgA deficiency.Antibodies: Structure, Types, and Therapeutic Roles

• Studies have shown that IgA is critical for clearing gastrointestinalviral pathogens such as rotavirus and preventing reinfection

.• Furthermore, selective IgA deficiency appears to be a significantrisk factor for recurrent chest infections, particularly in asthmaticpatients.

Antibodies in disease research andtreatment

Antibodies have emerged as a crucial and rapidly advancing class of therapeutics for a wide range of diseases,including cancer, autoimmune disorders, infectious diseases, and haematological malignancies.The 'big 5' that drive the therapeutic antibody industry are:• Infliximab and adalimumab are specific for tumour necrosis factor (TNF) and are used for treatingCrohn's disease, rheumatoid arthritis, and plaque psoriasis.

• Trastuzumab and bevacizumab are specific to human epidermal growth factor receptor 2 (HER2) and vascularendothelial growth factor A (VEGFA), respectively, and are used for the treatment of different cancers.

• Lastly, rituximab is a CD20-specific antibody used for both rheumatoid arthritis and non-Hodgkin's lymphom

Antibodies in diagnostics

Antibody-based assays, such as ELISAs, Immunocytochemistry, and flow cytometry offervaluable tools for diagnostic purposes

One of the most common uses ofmonoclonal antibodies is in simple diagnostictests, such as pregnancy tests. Duringpregnancy, the body produces humanchorionic gonadotrophin (hCG).

Pregnancytests can be done on blood or urine and usemonoclonal antibodies to detect the presenceof hCG. In the case of urine-based pregnancytests, if hCG is detected by the antibody, a positive band appears alongside the control,indicating pregnancy.

This is a readily available, low-cost rapid test that is usedevery day across the world