Humoral and Cell-Mediated Immunity

• Lecture discusses humoral and cell-mediated immunity

Adaptive Immunity

• It recognizes anything like foreign MHC proteins on cells or tissues
• It uses a large number of lymphocytes to recognize antigens
• Lymphocyte development includes B cell repertoire development via genetic rearrangements in bone marrow
• T cell repertoire development occurs through education in the thymus
• Communication between cells occurs using receptors and cytokines

Types of T Lymphocytes

• They are based on surface glycoproteins and functions
• Naive cells exist as CD8+ and CD4+ T cells

CD8+ T Cell

• Can become cytotoxic T cells
• These directly kill virally infected cells

CD4+ T Cell

• Can turn into Helper T cells
• Regulates activities of B cells and cytotoxic T cells
• Helper T cells types: Th1, Th2, and Tfl which activate adaptive immune responses
• Regulatory T lymphocytes repress adaptive immune responses

TCR binding to MHC

• MHC I binds to CD8 cells
• MHC II binds to CD4 cells, following the "Rule of 8"

Lymph Nodes

• Antigens are transported to T and B cells through draining lymph nodes
• Dendritic cells take up bacterial antigens from the skin
• The antigens then move to the draining lymphatic vessel, settling in T-cell areas
• T and B cells are located in distinct regions in lymphoid tissues

CD4 T Cell Activation

• Most T cells in 2' lymphoid tissues are Naive (never have seen an antigen)
• Naïve CD4 T cells activate through T Cell Receptor (TCR) signaling
• This happens once they associate with an antigen presenting cell (APC) and an antigen with MHC II
• The first step in inactivation is autocrine stimulation with interleukin-2 (IL-2)
• IL-2 causes antigen-specific CD4 T cells to proliferate
• TCR-signaling increases IL-2 sensitivity by upregulating the alpha subunit
• This creates a high-affinity IL-2 receptor

Effector CD4 T cell differentiation

• Activated clones of CD4 T cells differentiate into T helper subsets based on cytokine environment in the lymph node
• TH1 cells activate macrophages and are characterized by IL-12 and IFN-γ cytokines
• TH17 cells enhance neutrophil response and are characterized by IL-17 and IL-6 cytokines
• TH2 cells activate cellular and antibody response to parasites and are characterized by IL-4 and IL-5 cytokines.
• TFH cells activate B cells maturation of antibody response and are characterized by IL-21 cytokine.
• T regulatory cells (Treg) suppress other effector T cells and are characterized by TGF-β and IL-10 cytokines.

Th1 cell function

• Clones of activated Th1 cells interacts with macrophages expressing correct antigen on MHC II
• Selected by TCR, signaling mediated by Th1 cytokines and co-stimulatory molecules, like CD40 activation
• Macrophages upregulate proteins upon activation
• This increases the killing of intra-vesicular bacteria

Activation of B cells

• Naïve B cells in the lymph node recognize antigen collected by lymphatic duct.
• Antigen-BCR complexes internalize by receptor-mediated endocytosis.
• Antigens get processed and presented on MHC II
• The MHC II and peptide complex interacts with specific TCR on Tfh cell

B-cell activation

• Tfh cells recognize peptide and cytokines and CD40 cell and ligand interaction activates it from the B cell's antigen
• Tfh cell cytokines with CD40 and CD40L is required

B-Cells and Lymphoid Tissue

• Naïve B-cells circulate through secondary lymphoid tissue for stimulation
• The antigen is transported to a lymph node by a dendritic cell
• Afferent lymph distributes soluble antigen which washes over cells in the lymph node (LN)
• Naive B cells enter the LN through the bloodstream and enters the T cell area of cortex through HEV

B-Cells and Antigen

• If a the B Cell Receptor (BCR) is antigen specific, the B cell will processes the antigen and present it on MHC II, resulting in needing to find cognate T cell or die
• B cell moves to the T-cell region while looking.
• Once found cells stimulate each other leading to clonal expansion and producing clones of Tfh cells

Primary Focus

• Known as the primary focus, B cells produce small quantities of IgM
• Some B cells differentiate into IgM-producing plasma cells and migrate to medullary chords
• Short-lived plasma accumulate and produce soluble IgM and this drains with the lymph and enters the bloodstream.

Germinal Center

• Other B cells from the primary focus migrate to B cell region of the cortex along with Tfh cells continuing divide and form the germinal center
• Individual B cell clones undergoes somatic hypermutation and selection for affinity maturation of the BCR which takes several days

Germinal Center Operations

Affinity Maturation

• A process in which the B recognizes "good" mutation and undergoes cell division and somatic hypermutation to make BCR
• This is then processed by CD with a TCR and MHC II with FH that undergoes testing against antigens and undergoes selection
• A failed BCR with a "bad" mutation is rejected by cells with no BCR or MHC through apoptosis

B-Cells and Affinity Maturation

• In the germinal center proceeding with affinity maturation, medullary plasma cells produce low affinity IgM
• Short-lived plasma cells then start dying and blood IgM levels peak
• As optimal affinity maturation occurs B cells class switch from IgM to IgG and differentiate into long-lived IgG-producing plasma cells
• Long-lived migrate to bone marrow, produce large quantities of IgG which is released into the bloodstream, clear the blood, and antigens disappears from the LN
• Class-switched B differentiate into memory B cells which also distributing among lymphoid tissues

Ig Isotype Class Switching

• Cleavage at S region by AID putative endonuclease
• Can cause changes in C and Suy2b
• It is a concept

Steps of Humoral Response

• B cells enter lymph node seeking anitgen and cognate Tfh cells
• Antigen selected B cells proliferate.
• Select clones then differentiate into shot lived cells and mirgrate to the medulla of the node.
• The plasma cells then release IgM into blood and lymph.
• Select Clone generate in two migrate to the B together with cognate T to center germinal.
• individual B cell clones undergo somatic hypermutation to the I g gene or I g molecule to the antigen in a step affinity maturation.
• If they stimulated again.
• If now stimulated die.

Activation Results

• B cells with high affinity

B cell proliferation

• They do not secrete antibodies.
• They have BCRs to trigger production.
• They are long lived that go persist in the lymphoid tissue
• Production is initiated if antigen is trigger again.

Primary vs Memory Humoral Response

• A primary response occcurs with initial pathogen
• On the second time after is when a secondary response.
• Response caused by memory with the initial dose.
• This the basis of immunity and the reason for vaccinating.

T-Independent Antigens

• Can result with T cell help
• Can occur because repeat of same.
• No MHC Involvement
• Non-peptide antigens
• Mostly IgM produce
• Examples capsule or A and B antigens

IgA

• It's produced by TGF- B
• Transported by plgr

Viruses and Adaptive Responses

• Viruses infect cell as it synthesizes the Viral protein through ER
• This helps to transport class I to the class surface
• Cytotoxit T. Complex which is why it kills the cell.
• B cells use to neutralize abs.

CD8 Activation

• Is prime and I through MHC I
• Require II-2
• Cd8 up regulate

Effector CD8 T Kill

• Kill by using of CD8 T cells.
• Recognition of a virally infected epitheal cells kill

Killing Cells

• It's done by using Perforin-Granzyme Cytotoxic pathway
• It's done by using CD95 cytotoxic pathway

T Lymphocytes

Serial Killer

Memory

• Memory B subsets which is same to T cells clone
• Re-activation memory through presented antigen with HMC