The Immune System: Organs and Functions

Introduction to the Immune System

• The environment contains microorganisms, including bacteria, viruses, fungi, and parasites.
• Some microorganisms cause disease, but humans stay healthy due to defensive mechanisms.

Location of the Immune System

• The immune system is found throughout the body.
• Immune cells are in the blood and lymphatic circulatory systems, and lymphoid organs.

Primary Lymphoid Organs

• These are the sites where developing lymphocytes mature.
• Bone marrow: Located in the center of long bones, it's where hematopoietic cells complete differentiation and maturation, except for T cells.
• Thymus: A flat, bi-lobed organ above the heart where T cells complete maturation.

Secondary Lymphoid Organs

• Secondary lymphoid organs are where mature lymphocytes encounter pathogens or foreign molecules, and initiate adaptive immune responses.
• Spleen: Located on the left side of the abdominal cavity.
• Lymph nodes: Distributed throughout the body.

Lymphatic Circulatory System

• The lymphatic system enables lymphocytes and proteins to circulate and interacts with the blood circulatory system.
• Lymph fluid drains from tissues into lymphatic capillaries and lymph nodes, similar to blood but lacks red blood cells and platelets.
• This fluid returns to the bloodstream via the thoracic duct near the heart.

Three Levels of Defense Against Infection

• Anatomical and Physiological Barriers: Physical barriers include intact skin and mucosal surfaces. Chemical defenses include stomach acid, lysozyme, and antimicrobial secretions.
• Innate Immune Responses: These are fast and non-specific, and involve phagocytosis and complement protein activation, limiting infection spread and resolving infections.
• Adaptive Immune Responses: These re slower but highly specific and involve antibody-mediated and cell-mediated responses.

Cells of the Immune System

• Major blood cell populations include erythrocytes (red blood cells) for oxygen transport and leukocytes (white blood cells) that form the immune system.
• Hematopoietic Stem Cells (HSCs): These self-renewing stem cells are found in bone marrow, umbilical cord blood, and circulating blood, and give rise to all blood cells, including immune cells.

Leukocyte Classification

• Myeloid Cells: (Innate Immune Response) Include monocytes that differentiate into macrophages, mast cells, and granulocytes (neutrophils, basophils, eosinophils).
• Lymphoid Cells: (Adaptive Immune Response) Consist of cytotoxic T cells (CTLs), T helper (Th) cells, T regulatory (Treg) cells, and B cells.
• Natural Killer (NK) Cells: Participate in innate immunity.
• Dendritic Cells: Link innate and adaptive immunity, activate T cells to initiate adaptive responses, and are derived from lymphoid or myeloid cells.

Summary

• The immune system defends the body through three layers of defense: anatomical barriers, innate immunity, and adaptive immunity.
• Anatomical barriers are always present.
• Innate immunity is fast and non-specific, controlling and eliminating most infections.
• Adaptive immunity is slower but highly specific to pathogens.
• The immune system consists of various cells derived from hematopoietic stem cells, including neutrophils, macrophages, dendritic cells, T cells, and B cells.
• Key immune organs include primary lymphoid organs (bone marrow and thymus) and secondary lymphoid organs (spleen and lymph nodes).

Innate Immune Responses - Part 1

• Innate immunity acts immediately to remove pathogens without causing disease in the host, while adaptive immune responses are required if innate responses are overwhelmed.
• Innate immunity distinguishes "dangerous" from "innocuous" elements using Pattern Recognition Receptors (PRRs) that recognize Pathogen-Associated Molecular Patterns (PAMPs).

Recognizing a Pathogen / PAMPs

• PAMPs are not produced by the host organism, shared by large groups of pathogens, stable with minimal mutation, essential for pathogen survival, and are recognized by PRRs in the innate response.
• Examples of PAMPs include peptidoglycan in Gram-positive bacteria and lipopolysaccharide (LPS) in Gram-negative bacteria.

Toll and Toll-like Receptors (TLRs)

• The two main types of membrane PRRs are phagocytosis receptors (for internalizing particles) and Toll-like Receptors (TLRs) (to identify pathogens).
• The Toll receptor family is evolutionarily conserved from invertebrates (Drosophila melanogaster) to mammals.
• Mammalian TLRs resemble Drosophila Toll in structure and function, containing an extracellular leucine-rich domain (recognizes PAMPs), a transmembrane domain, and a cytoplasmic Toll/Interleukin-1 receptor (TIR) domain.
• Mammals have 13 described TLRs, with 11 functional in humans.
• TLRs can function as homodimers or heterodimers, increasing the range of recognized PAMPs, and TLR activation leads to NF-κB activation, a key transcription factor for antimicrobial peptides.

The Complement (C') System

• The complement system consists of plasma proteins that attack extracellular pathogens in a cascade of reactions, involving cleavage of proteins to amplify the response.
• Complement activation pathways include the Classical pathway (triggered when antibodies bind to a pathogen) and the Alternative pathway (directly activated when complement proteins bind to bacterial surfaces, bypassing antibody recognition).

Key Steps in Complement Activation

• Formation of C3 convertase: Cleaves C3 into C3a and C3b and C3b binds to the pathogen and recruits other complement proteins to form C5 convertase.
• Activation of the inflammatory response: C3a and C5a bind to blood vessel receptors, increasing permeability and facilitating immune cell recruitment and stimulate mast cells and macrophages to release histamine and TNF-a.
• Opsonization and phagocytosis: C3b coats pathogens, enhancing their recognition and engulfment by phagocytes.
• Membrane Attack Complex (MAC) formation: C5b recruits proteins to form a pore in the pathogen's membrane, leading to lysis and death.
• The innate immune response is fast, non-specific, and triggered by pathogen components.
• PAMPs bind to PRRs on innate immune cells, leading to phagocytosis or cytokine production.
• Inflammation occurs when mast cells release histamine, increasing vascular permeability. Macrophages release cytokines to recruit immune cells and enhance pathogen destruction.
• The complement system enhances immune defense through inflammation, opsonization, and direct pathogen lysis.
• Dendritic cells link innate and adaptive immunity, highlighting the importance of a strong innate response for effective adaptive immunity.

Innate Immune Responses - Part II

• Innate immunity acts immediately to remove pathogens without causing disease, but adaptive immunity is required if innate defenses are overwhelmed, bypassed, or evaded.
• Inflammation is caused by physical/chemical insult or infection with microorganisms.
• Bacterial infection activates the alternative complement pathway and stimulates tissue-resident macrophages that detect PAMPs.
• Acute inflammation is of short duration, and is the initial response to infection with minimal tissue damage.
• Chronic inflammation is of long duration and involves activate macrophages and T cells, which leads to significant tissue destruction due to oxygen metabolites, nitric oxide (NO, and proteases).
• An example of the inflammatory response is a finger cut infection

Recognition and Phagocytosis

• Bacteria is recognized by tissue-resident macrophages, where a pattern recognition receptor (PRR) binds to the bacterium to trigger phagocytosis.
• Toll-like receptors (TLRs) bind to PAMPs and the interaction activates NF-kB a transcription factor.
• NF-kB activates genes for TNF-α, IL-1, IL-6 (pro-inflammatory cytokines), and CXCL8 (chemoattractant) guides phagocytic cells to the infection site.

Initiation of Inflammatory Response

• Mast cells release histamine and inflammatory molecules upon injury.
• Histamine dilates blood vessels and increases blood flow
• Cytokines from macrophages increase blood vessel permeability and induce expression of adhesion molecules on endothelial cells.
• Increased permeability causes fluid, proteins, and cells to leak into tissue causing swelling and pain.
• Adhesion molecules allow leukocytes to stick to endothelial cells and squeeze through gaps in extravasation while CXCL8/IL-8 guides leukocytes to bacterial site.
• Neutrophils start phagocytosis, and monocytes mature into macrophages before effective phagocytosis.

Recruitment and Phagocytosis

• Neutrophils and monocytes are recruited hours after infection, and Bacteria get engulfed into a phagosome.
• The Phagosome is acidified, fuses with lysosomes to form a phagolysosome that utilizes nitric oxide superoxide anion, hydrogen peroxide, defensins, and proteases to kill and degrade bacteria.

Clotting and Skin Repair

• Coagulation mechanisms are activated to wall off infection and immobilize bacteria, and later skin repair mechanisms are activated.

Pus Formation

• Pus happens due to the aggregation of macrophages, neutrophils, dead skin cells, dead bacteria, and plasma.

Summary

• Innate Immune Response is a fast and non-specific reaction which is triggered by pathogen components.
• Pathogens are recognized as “foreign” or “non-self” by PAMPs which then trigger immune production by the PRRs.
• Inflammation begins after tissue damage causing mast cells to release histamine, which increases vessel permeability, where fluid, cells, and proteins leak into tissues and cause swelling.
• Macrophages then release cytokines and recruit more cells, phagocytose and destroy pathogens, and coagulation proteins seal the infection area enhancing the complement activation and pathogen destruction.

Antigen Processing and Presentation

• Antigen presentation constitutes displaying peptides derived from pathogens or proteins on dendritic cell surface for T cells, and MHC proteins provide the structure for displaying antigenic peptides to T cells.
• Two main types of MHC proteins: MHC class I and MHC class II, with both types having grooves to bind peptides.
• MHC Class I proteins are expressed on all nucleated cells.

MHC Class I

• Structure in MHC-1 consists of a transmembrane α chain non-covalently associated with β2-microglobulin, with a peptide-binding groove in the α chain.
• Peptide length is approximately 8-10 amino acids and binds to the nascent MHC class I protein.

MHC Class II

• MHC Class II Proteins are expressed on antigen-presenting cells (dendritic cells, B cells, macrophages, thymic epithelial cells).
• Structure of MHC-II consists of two non-identical transmembrane polypeptide chains (α and β chains), with the peptide-binding groove between the α and β chains, and a peptide length of at least 13 amino acids.

Antigen Processing and Presentation Breakdown

• Antigen Processing: Degradation of proteins into peptide fragments.
• Antigen Presentation: Binding and display of peptides on MHC proteins.

MHC Class I Pt 2

• From cytoplasmic proteins ,MHC class I proteins degraded by the proteasome in the cytoplasm.
• TAP proteins transport peptides to the endoplasmic reticulum (ER).
• Peptide binds to nascent MHC class I protein.
• Results in: MHC class I-peptide complexes transported to the cell surface.

MHC Class II Pt. 2

• From extracellular proteins that are taken up by endocytosis or phagocytosis.
• MHC class II proteins with invariant chain (li) leave ER in vesicles.
• Endosome/phagosome fuses with lysosomes, where proteases degrade proteins into peptides.
• Peptides stay inside vesicles, not entering the cytoplasm.
• MHC class II/li complex fuses with vesicle containing peptide fragments in the MIIC region.
• Invariant chain is degraded to CLIP, occupying the peptide-binding site.
• CLIP replaced by peptide fragment.
• Results in MHC class II-peptide complexes being transported to the cell surface.

Cross-Presentation

• MHC class I proteins display peptides from exogenous proteins.
• Dendritic cells are capable of cross-presentation using this process.
• A process in which Antigen enters through endosome/phagosome and Vesicle content is diverted to the proteasome, followed by processing via the endogenous pathway leading to Dendritic cells presenting peptides from exogenous antigens on both MHC class I and MHC class II proteins.

MHC Diversity Summary

• MHC genes are polygenic, which means that Multiple genes encode proteins with similar functions
• MHC class I proteins: HLA-A, HLA-B, HLA-C and are expressed on all nucleated cells.
• MHC class II proteins: HLA-DP, HLA-DQ, HLA-DR and are expressed on antigen-presenting cells.
• Co-dominant expression: Both maternal and paternal alleles are expressed.
• Polymorphism: Many different alleles exist for each MHC gene
• Importance of polymorphism is that Different alleles enable recognition of a broad range of pathogens and A reduction in MHC polymorphism can predispose to infectious disease.
• Additionally, the combination of HLA proteins defines tissue type and are important for organ transplantation.

Summary

• MHC proteins allow cells to communicate with T cells.
• MHC class I are composed of a chain and ẞ2-microglobulin and are found on all nucleated cells.
• MCH class II are Dimers of a and ẞ chains are found on antigen-presenting cells.
• Antigenic peptides work via MHC class I which uses the endogenous pathway to present peptides from intracellular proteins and through MHC class II which use the exogenous pathway to present peptides from extracellular proteins or Cross-presentation in which Dendritic cells present exogenous antigens on both MHC class I and MHC class II.

T Cells of Adaptive Immunity - Introduction

• The adaptive Immune system is activated if innate immunity cannot eliminate an infection, and is last line of defense.
• The immune system uses antibodies and T cells.
• T cells are the primary defense against viral infections and intracellular bacterial pathogens (Mycobacterium tuberculosis).

T Cell Receptor (TCR) Structure

• TCRs are membrane-bound protein composed of two different linked polypeptides.
• TCRs do not secrete but involve rearrangement of TCR gene segments, creating unique antigen specificity.
• TCR complexes consist of an antigen-binding subunit of TCR as well as a signaling subunit and co-receptors.
• Corecptors can be CD4 to find helper cells or CD8 to find Cytotoxic T cells.
• Co-receptor binding increases affinity between T cell and antigen-presenting cell.
• TCR contain one antigen molecule, with about 30,000 identical copies on the surface of a mature T cell.

T Cell Function

• TCR recognizes peptides bound to MHC proteins, not native/unprocessed antigens.
• CD3 complex transmits activation signals into the T cell.

T Cell Development

• All immune cells originate from hematopoietic stem cells and some progeny specialize into common lymphoid progenitors, and differentiate into T cell precursors that migrate to the thymus for maturation developing in TCR expression alongside CD4/CD8.
• Developing thymocytes then undergo positive and negative selection.

T Cell Selection

• Positive selection ensures TCRs interacts with MHC proteins and is mediated by thymic cortical epithelial cells
• Negative Selection eliminates self antigens through self-reactive elimination.
• Thymecytes unable to bind MHC die of neglect.

Negative T Cell Selection

• Self reactive T cells that bind MHC + self-peptide die by high affinity, first through thymic cortical epithelial cells, marrow-derived macrophages/dendritic cells or medullary thymic epithelial cells (mTECs).
• AIRE ensures only thymocytes survice withe weak binding to MHC + self peptides.

T Reg

• T regulatory cells regulate cell-reactive T cells that espace negative selection and develop in the thymus with high affinity and expressed levels of CD25.
• Function suppresses immune responses and prevents diseases.

Summary

• TCR contains on V region and one C region per a/B chain.
• T cell development starts in bone marrow and matures in Thymus.
• T cells become cytotoxic, helper or regulatory cells
• Selection process involves Positive to secure binding and negative to eliminate antigens.

Antigen-Presenting Cells and T Cell Activation - Introduction

• Dendritic cells act the liaison between innate and adaptive immunity and are found in all immune-patrolled tissues that assist in transporting derived pathogen cells.
• Langerhans cells are immure dendritic cells in the skin, are efficient at processing, but cannot activate T cells until matured by Pattern Recognition Receptors.
• Dendritic cells provide a snapshot and initiate Adaptive Response to aide.

Co stimulatory Properties

• Only preofessional APC cells can have MHCs and co -stimulatory signals that activiate the B7 proteins and fully activate naive T cells.
• Types include Dendritic Cells that are potent activators, macrophages and B cells that upregulate functions
• T cell subsets activate depending on interaction of aMHC to make T cell activated

T Cell Activation

• T Cell subsets include CD4 for Helper function, CD8 for Cytotoxic, which depends on proper signals.
• TCR binding enables Corecptor linking, costim and cytokine signaling which either causes anergic or cytokine production.
• Signal 1 without Proper signals will results into Clonal Anarchy.
• helper/cytokines assists in killing and differentiation, but are dependent on the source of the activating cell, APC's and CTL cells differ in IL-8.

Overview of Adaptive Response

• Adaptive Immunity: Adaptive immunity, requiring innate immunity to begin, is triggered after its cellular peptide signaling activates the adaptive cells.
• B cells versus T cells: Adaptive immunity consists of:
• B cells: antibodies to fight bacteria/virus and cellular response
• T cells: cellular response to attack
• B cell creation: Created in common lymphoid progenitors
• T cell creation: Precursors migrate into the cortex.

Learn about the immune system, its location throughout the body, and the functions of primary and secondary lymphoid organs. Discover where immune cells reside in the circulatory systems and lymphoid organs. Understand the roles of bone marrow, thymus, spleen, and lymph nodes.