Made possible through somatic hypermutation and VDJ recombination

When an antigen enters the body, B and T cells are activated. These cells have specialised receptors in their surface designed to recognise specific antigens. When a B or T cell encounters its matching antigen, it activates and immune response.

Antigen recognition is highly specific. Each B and T receptor has a unique shape that can only bind to a particular antigen. This ensures that the immune system only attacks foreign invaders, and not the body's own healthy tissues.

The immune system can adapt and remember past encounters. when a B or T cell is activated by an antigen, it clones itself to generate a large army of identical cells to target that particular antigen. this creates immunological memory, allowing the immune system to respond swiftly, and efficiently in the future if the same pathogen tries to enter the body.

through processes referred to as clonal selection and clonal expansion

1. Recognise and bind to invading microorganisms.
2. Eliminate the invading microorganism.

Play a crucial role in antigen recognition and B cell activation. They bind to the antigens presented on the surface of pathogens, and initiate signaling pathways that leas to B cell activation, and/or differentiate into antibody-secreting plasma cells. The binding of antigens to membrane-bound antibodies triggers processing of antigens for presentation to helper T cells. This would make the immune response stronger against the attacker.

B cells are stimulated to produce this type of antibodies these are referred to as immunoglobulin.

These antibodies are released into the bloodstream, and tissues by plasma cells. These are the soluble form of antibodies, which we refer to as immunoglobulins. They play a crucial role in humoral immunity. They are divided into various classes (Ig G, Ig A, Ig M, Ig D, Ig E). These antibodies contribute to the adaptive immune response by providing long-lasting immunity through memory B which attack the attacker quicker when they try to attack the body again.

Because it determines what immune cells and molecules are recruited by the antibody to help destroy and remove a pathogen.

Different isotypes appear at different stages of an immune response.

Each of them differ based on their differences in the amino acid sequences found in the constant region.

Antibody classes also differ based on their valency

Abundantly found in internal body fluids

Primarily produced in and during secondary immune response

Ig G1, Ig G2 and Ig G3 are found more than Ig G4 as Ig G1, Ig G2 and Ig G3 are responsible for activating the complement pathway

They also bind to the invading microorganisms so that they can be opsonised by macrophages and neutrophils to be phagocytosed and killed.

This is the only antibody capable of crossing the placenta to give passive immunity to fetus (all 4 subclasses are to cross into fetal circulation).

Subdivided into Ig G1, G2, G3, and G4

Secretory Ig A is safe from proteolytic lysis (due to the presence of the J-chain)

Key antibody for primary immune responses (high amounts in body could mean an infection)

Usually found in smallest amount in the body (on surface of mast cells and basophils)

Responsible for the trigger and release of inflammatory mediators in the body.

High numbers of Ig E are seen in people with allergies

Works together with mast cells to act as "gatekeepers" (regulating the exit of cells into extravascular sites).

Stages strong immune responses against parasitic infections.

This is then followed by a healing mechanism to help the body recover.

Intraepithelial T lymphocytes kill microbes and infected cells

-most abundant in the body, stimulated by colony stimulating factors

Functions:

1. ingest and destroy microbes
2. clear dead tissues and initiate tissue repair
3. produce cytokines
   

Classical activation(M1 macrophages) or alternative activation (M2 macrophages)

produced in bone marrow, released to systemic circulation with granules inside

-Small proteins, not antibodies Definitions: Hormone like secreted proteins that function as mediators of immune and inflammatory reaction

5 types:

• Chemokines
• Interferons
• Interleukins
• Lymphokines
• tumour necrosis factor

Functions:

1. Act through cell surface receptors for an immune response
2. Moderate balance between humoral and cell-based immune response
3. Regulate development and production of certain other immune cells

Interactions:

1. Pleiotrophic - different effects on different type of target cells
2. Redundant - multiple cytokines have same effect
3. Synergic- cooperative effect of multiple cytokines
4. Antagonistic- Inhibition of 1 cytokines effects by another
5. Cascade induction- step-feed forward mechanism for amplified production of particular cytokine

Cytokines in Innate:

1. TNF-α
2. IL-1
3. IL-10
4. IL-12
5. INF-α
6. INF-g

Cytokines in Adaptive:

1. IL-2
2. IL-4
3. IL-5
4. TGF-β
5. IL-10
6. IFN-γ
   

Stimulate haematopoietic cells to differentiate into specialised cells

Cytokines:

1. Interleukins (ILs)
2. Colony-stimulating factors (CSFs)
3. Interferons
4. erythropoietin (EPO)
5. Thrombopoietin (TPO)

Bind to receptors on haematopoietic stem cells (HSCs) and regulate functions like quiescence, self-renewal, differentiation, apoptosis and mobility

Genes encoding the variable (V), diversity (D), and joining (J) regions of the TCR alpha and beta chains undergo rearrangement.

One V segment, one D segment (if present), and one J segment are randomly selected and joined together to form the variable region of the TCR gene for both the alpha and beta chains

TCRs do not undergo somatic hypermutation, but TCR diversity is further enhanced by the combinational diversity resulting from the pairing of the alpha and beta chains

Genes encoding the variable (V), diversity (D), and joining (J) regions of the BCR light and heavy chains undergo rearrangement.

One V segment, one D segment (in the heavy chain), and one J segment are randomly selected and joined together to form the variable region of the Ig gene.

Variable regions of the Ig genes undergo random mutations

Gene encoding antigen receptors are split into multiple segments: Variable (V), Diversity (D - only present in T cells), and Joining (J) segments. Each cell has a large pool of these segments.

Enzyme complexes (RAG1 and RAG2) that act like molecular scissors, initiating the recombination process

Specific DNA sequences flanking the V,D, and J segments that guide RAG where to make the cuts.

RAG proteins recognises the RSS flanking the V, D, and J segments. They introduce precise double-stranded breaks at specific location within these sequences. This creates "signal ends" and "coding ends" on the cleaved DNA segments.

The coding ends (where the variable region of the antigen receptor is encoded) undergoes a unique modification. They bend and fold back onto themselves, forming hairpin structures. This step is crucial for the proper joining of the segments later.

The coding ends from different V, D (for T cells), and J segments are brought together. The cellular machinery recognises them and precisely joins them. Meanwhile, the signal end, which lacks the hairpin structure, are rejoined with minimal modifications.

During the joining process, enzymes can insert or delete a few nucleotides at the junctions where the V, D (for T cells), and J segments come together. this slight randomness adds another layer of diversity to the antigen receptor.

Not all rearrangements are successful. the cells checks if the joining process resulted in a functional antigen receptor sequence. If not, the process might be repeated with different segments. Only lymphocytes with functional antigen receptors will mature and contribute to the immune response

An extension from VDJ recombination (through which the DNA of the immunoglobulin is created) wherein through class switching the isotype of the immunoglobulin is being chosen to be either IgM-IgD, IgG, IgE or IgA

B cell development begins from hematopoietic stem cells (HSCs) in the bone marrow. Immature B cells, also called pro-B cells, undergo rearrangement of their immunoglobulin heavy chain (IgH) genes to form functional heavy chains. the successful rearrangement of the IgH genes leads to the expression of pre-B receptor (pre-BCR) on the surface of pre-B cells.

Pre-B cells that express functional pre-BCRs undergo further maturation into immature B cells. Immature B cells express both IgM and IgD on their surface and undergo an additional process of selection and maturation to become mature B cells. During this stage, immature B cells undergo negative selection .

Mature B cells that successfully complete maturation in the bone marrow migrate from the bone marrow to peripheral lymphoid organs, including the spleen and the lymph nodes, via the bloodstream.

In the peripheral lymphoid organs, mature B cells encounter antigens derived from pathogens or foreign substances. Recognition of antigens by B cell receptors (BCR) leads to B cell activation, proliferation, and differentiation into antibody-secreting plasma cells or memory B cells.

Activated B cells differentiate into plasma cells, which are specialised to produce and secrete large quantities of antibodies specific to the encountered antigen. Some activated B cells differentiate into memory B cells, which have a longer lifespan and provide a rapid and enhanced secondary immune response upon re-exposure to the same antigen.

Plasma cells secrete antibodies, which circulate in the blood stream and lymphatic system, targeting and neutralising pathogens or foreign substances. Memory B cells remain quiescent but can quickly respond to subsequent encounters with the same antigen, leading to a faster and more robust immune response upon re-exposure.

T cell development begins with the migration of progenitor cells from the bone marrow to the thymus via the bloodstream. Progenitor cells entering the thymus are called thymocytes.

Thymocytes then undergo positive selection. Positive selection ensures the survival and maturation of thymocytes expressing T cell receptor (TCRs) that are capable of weakly recognising self-antigens. This is so that they don't attack upon normal body cells expressing such self-antigens. Thymocytes that successfully undergo positive selection differentiate into CD4+ helper T cells or CD8+ cytotoxic T cells.

After positive selection, Mature thymocytes undergo negative selection. Negative selection involves the elimination of thymocytes that strongly recognises self-antigens. Those negatively selected under programmed cell death referred to as apoptosis.

Thymocytes that successfully pass through positive and negative selection differentiate into mature T cells with diverse TCR specificities. They exit the thymus and migrate to peripheral lymphoid organs, such as lymph nodes and the spleen, via the bloodstream.

In the peripheral lymphoid organ, mature T cells encounter foreign antigens presented by antigen-presenting cells (APCs) such as dendritic cells. Recognition of such antigens by TCRs, together with co-stimulatory signals, leads to T cell activation, specialised differentiation of T-cells to helper T cells (Th1, Th2, Th17) or cytotoxic T cells (CD8+ T cells).

Some activated T cells differentiate into memory T cells, which provide long-term immunity against previously encountered pathogens or antigens.

Proteins produced by hepatocytes (liver cells).
Breakdown into 2 during enzymatic cleavage:
-smaller subunit-a
-bigger subunit-b
Except for C2 (smaller-b, bigger-a)

Once C5b activated, membrane-attack-complex assembled

Factor D cleave factor B to give C3b-Bb complex (C3 convertase), which then activate C5 convertase

1. Opsonisation- Microbes coated by C3b are recognised by phagocytes for phagocytosis

2. Cell lysis- MAC induces osmotic lysis of microbe-coated cells

3. Inflammation -residual fragments like C3a and C5a act as chemotactic agents for neutrophils, release inflammatory mediators

4. Initiates-B cell responses and antibody production- complement proteins bound to antigen-antibody complexes are recognised by APCs for B-cell activation and selection of high affinity B cells

Differentiated into antibody secreting plasma

Once ITAMs are phosphorylated, signal transduction is triggered through the cytoplasm into the nucleus of B cells.

B-cells respond directly to antigenic stimulation without antigen processing and presentation by APCs or T cell

Result in production of antibodies with lower affinity and shorter duration

Microbial antigens are: Polysaccharide, glycolipids, nucleic acids. Usually with multiple repeating epitopes

Most B cells differentiated to plasma cells (IgM produced)

These antigens referred to as T dependent or Thymus-dependent (Td antigens)

Th2 recognised the same antigen that B cell recognised. Therefore enable both Th2 and B cell to come close together

Th2 expressed CD40 ligand which bind to CD40 expressed on B cell to form CD40-CD40L complex

IL-4 produced by Th2 helper cells and lead to proliferation of B cell to become plasma cells and memory cells

Only one antibody class is expressed by B cell at a time

Only seen in foreign antigens that express protein antigen, where T-cell dependent B-cell activation takes place

Long-lived memory cells move to periphery

Attacking of pathogen is faster and more efficient

CD3 molecules are responsible for proximal signalling events

CD3 assembled with TCR possess characteristic sequence motif for tyrosine phosphorylation, immuno-receptor tyrosine-based activation motif (ITAMs)

stabilise (or secure) the binding of T cells to respective APCs

leave secondary lymphoid organs to look for microbes found in other sites of the body

remain inside the lymphoid organs to help B-cells in the production of antibodies

secrete cytokines

engage phagocytes

CTLs recognise class I MHC-peptide complex leading to activation of signal transduction pathway -> exocytosis of CTL's granules

enzymes that cleave and activate enzyme, caspases which induce apoptosis

insert into endosomal membranes and facilitate movement of granzymes into cytoplasm

activated CTLs express Fasligand protein - binds to death-inducing receptor Fas(CD95)

Macrophages express various pattern recognition receptors (PRRs) which can recognise specific molecular patterns associated with pathogen triggering a signalling cascade

Binding of antigens to PRRs initiates intracellular signalling cascades -> activation of transcription factors

Activation of transcription factors leads to the expression of genes involved in inflammation and immune responses

Activated macrophages increase their microbicidal activity, including phagocytosis, production of reactive oxygen species (ROS) and reactive nitrogen intermediates (RNI), and secretion of antimicrobial peptides

Activated macrophages also play a crucial role in antigen presentation, presenting antigens to T cells

The alternative pathway can be initiated by signals associated with tissue damage, inflammation or presence of foreign substances in the tissue

While the alternative pathway does not rely on specific antigen recognition like classical pathway, macrophages still utilise PRRs to detect signals

Activation of PRRs triggers intracellular signalling cascades within macrophages -> change in gene expression and functional properties

Activated macrophages exhibit distinct gene expression profile -> produce anti-inflammatory cytokines

Macrophages play essential roles in tissue repair, remodelling and promote tissue healing

engulf & process antigens -> dispplay fragments on cell surface with MHC

T cells recognise antigen presented by APC -> activate T cells

T cell undergo clonal selection followed by expansion to multiply rapidly

performed by T helper cells & cytotoxic T cells

some activated T cells differentiate -> memory T cells for rapid response upon re-exposure

activated T cells produce IL-2 which activates clonal expansion

aid in B cell activation for antibody production

stimulate phagocyte-mediated ingestion & killing of microbes

stimulate phagocyte-independent, eosinophil-mediated immunity -> effective against helminthic viruses

station at mucosal barriers to remove pathogens trying to enter at those portals of entry

responsible for massive clonal expansion when the same foreign antigens attack

responsible for effector mechanisms when foreign antigens come into contact

does not enter systemic circulation but initiates first response to foreign antigen -> activate other memory cells

when lymphocytes roll around blood vessels (venules), a reaction is triggered between chemokines (in endothelial layer of venules) & their respective chemokine receptors (on lymphocytes)

this adhesion molecules cling onto walls of the vessels to congregate and pool lymphocytes at that area

peptide-binding cleft between a1 and a2

CD8 T cell co-receptor binding site -> a3

peptide-binding cleft between a1 and β1

CD4 T cell co-receptor binding site -> a2 and β2

Interaction between CD8+ on surface T cell & non-peptide binding regions on MHC I

Interaction between CD80/86 on APC & CD28 on T cell surface

Includes production of cytokines by APC which fully activates the T cell to provide a specific response

Antigens, eg. proteins from pathogens, are taken up by APCs, through phagocytosis, endocytosis or pinocytosis

Once inside the APC, antigens are degraded by enzymes within specialised cellular compartments - endosomes/lysosomes

MHC II molecules are synthesised in the endoplasmic reticulum (ER) & then transported to endosomes within the cell. In the compartments, MHC II molecules bind to a protein - invariant chain (li) to stabilise & prevent premature binding of self-antigens

Within the endosomal or lysosomal compartments, the invariant chain is cleaved, leaving a
small fragment called the class II-associated invariant chain peptide (CLIP) bound to the MHC II binding groove.

Meanwhile, the processed antigen peptides generated from the degraded pathogen proteins bind to MHC II molecules in place of the CLIP fragment. Loading process facilitated by protein complex - HLA-DM molecule. HLA-DM catalyses the exchange of CLIP for antigenic peptides, ensuring that only peptides with high affinity for MHC II are presented.

The MHC II molecules, now bound to antigenic peptides, are transported to the cell
surface and expressed on the APC's plasma membrane. Here, they present the antigenic peptides to CD4+ T cells,
also known as helper T cells. This is then followed by T cell activation.