Immunology Course Overview

Immunology is a branch of biological science that studies the immune system in all organisms. It deals with the functioning of the immune system, its disorders, and its role in various diseases.

Immunology Course Overview

The immunology course covers major concepts of immune response using illustrations, figures, diagrams, and tables. Key notions will be highlighted for better retention.

Course Chapters

• Chapter 1: Structure of the Immune System

• Chapter 2: Lymphocyte Development

• Chapter 3: Major Histocompatibility Complex (MHC) and Antigen Presentation

• Chapter 4: Infectious Diseases and Vaccination

Key Inquiry Areas

• How does the Immune System function?

  • Constituents of the Immune System

  • Distribution in the organism

  • Interactions between constituents

• How does the Immune System recognize foreign bodies?

  • Major Histocompatibility Complex and antigen presentation

• How do Immune Cells develop?

  • Development of T and B lymphocytes

Recommended Reading

• Roiitt's Essential Immunology by Ivan M Roitt & Peter J Delves

• Owen Kuby Immunology by Owen Punt Stranford

• Understanding Immunology by Peter Wood

• Fundamental Immunology by William E. Paul

• Janeway's Immunobiology by Kenneth Murphy

Chapter 1: Structure of the Immune System

The immune system consists of various cells and organs working together to protect the body against pathogens.

Cells of the Immune System

1. Hematopoietic Stem Cells (HSCs): These are multipotent adult stem cells, the origin of all immune cells. They possess:

   • The capacity to differentiate into diverse immune cell types.

   • The capacity for self-renewal.

   HSCs reside and differentiate primarily in the bone marrow. The maturation process of HSCs into immune cells is called Hematopoiesis.

2. Myeloid Cells

3. Lymphoid Cells

Regulation of HSCs

The number of HSCs is tightly regulated by a balance between division, differentiation, and cell death.

• At rest (Homeostasis): HSCs are quiescent.

  • A small fraction divides into identical daughter cells.

  • Another fraction develops into progenitor cells for various specialized immune cells, losing their self-renewal capacity.

• During Immune Response to a Pathogen: HSCs show a high proliferation capacity.

Lineage Choice Regulation

The choice of hematopoietic lineage is regulated by:

1. Genetic Modifications: Transcription factors such as:

   • GATA-2: Involved in the development of all hematopoietic lineages.

   • Ikaros: Involved in myeloid and lymphoid lineage development.

   • Notch: Involved in the choice between T and B lymphocytes.

2. Environmental Modifications:

   • For example, an infection can induce the release of cytokines, favoring myeloid lineage development.

Immune System Organs

Primary Lymphoid Organs

These are sites for the development and maturation of lymphocytes.

1. Bone Marrow (MO): Site for maturation of all erythro-myeloid cells and B cells.

2. Thymus: Site for maturation of T cells.

Secondary Lymphoid Organs

These are the sites where lymphocytes encounter antigens.

They all share key properties:

• Possess anatomically distinct regions where B and T cells are activated.

• Contain lymphoid follicles for B cell maturation.

1. Lymph Nodes: Lymphocytes (T Helper and B cells) interact with Antigen-Presenting Cells (APCs), inducing:

   • Proliferation and differentiation of B and T cells.

   • Generation of T and B memory cells.

   Memory cells can be:

   • Central memory cells: Reside in secondary lymphoid organs.

   • Effector memory cells: Migrate to the site of initial infection.

2. Spleen: Filters blood, removes old red blood cells, stores platelets, and serves as a site for immune responses.

3. MALT (Mucosa-Associated Lymphoid Tissue): Lymphoid tissues located in mucous membranes, such as Peyer's patches in the small intestine.

Tertiary Lymphoid Tissues

These are sites of infection that organize and maintain the immune response. Activated lymphocytes from secondary lymphoid organs can return to these sites as effector cells or memory cells. They generate a microenvironment that organizes returning lymphocytes.

Types of Immune Cells

Myeloid Cells

These include granulocytes (neutrophils, eosinophils, basophils), monocytes, macrophages, and dendritic cells.

• Neutrophils: Characterized by multi-lobed nuclei and granules.

• Monocytes: Circulate in the blood and differentiate into macrophages and dendritic cells in tissues.

• Macrophages: Phagocytic cells involved in antigen presentation.

• Dendritic Cells (DCs): Highly effective antigen-presenting cells.

• Megakaryocytes: Large bone marrow cells responsible for producing platelets.

Lymphoid Cells

These include B lymphocytes, T lymphocytes, and Natural Killer (NK) cells.

• B Lymphocytes (B cells):

  • Maturation occurs in the bone marrow in humans (initially identified in the Bursa of Fabricius in birds).

  • Possess a B-cell receptor (BCR) in the form of immunoglobulin.

  • Increase specificity through Somatic Hypermutation.

  • Produce antibodies of different classes (Class Switching).

  • Activated into effector cells called Plasma cells, which specialize in antibody secretion and lack BCRs.

• T Lymphocytes (T cells):

  • Maturation occurs in the Thymus.

  • Express a unique receptor called TCR (T-Cell Receptor).

  • TCR recognizes only peptides presented by the MHC (Major Histocompatibility Complex) on the surface of APCs.

  • Exist in two main categories:

    • Helper T cells ( or CD4+): Recognize antigens presented by APCs in complex with MHC class II. Activated CD4+ cells proliferate and differentiate into:

      • : Immune response to intracellular pathogens.

      • : Immune response to extracellular pathogens.

      • : Secrete IL-17, immune response against fungi.

      • : Play a role in B cell maturation.

    • Cytotoxic T cells ( or CTL or CD8+): Recognize non-self antigens in complex with MHC class I.

  • The ratio of CD4+/CD8+ cells in normal mouse blood is 2:1.

• Regulatory T cells (Treg):

  • Important for suppressing auto-reactive responses and limiting normal immune reactions to pathogens.

  • Are CD4+ and CD25+ on the surface, and express the Foxp3 protein in their cytoplasm.

  • Can be "Natural Treg" (develop in the thymus from auto-reactive cells) or "Induced Treg" (induced by antigen presence at infection sites).

• Natural Killer (NK) cells:

  • Highly effective cytotoxic lymphocytes, part of the innate immune system.

  • Express the NK1.1 receptor and contain cytotoxic granules.

  • Eliminate cells that do not express MHC I molecules.

  • Their activity is inhibited by contact with MHC receptors.

  • Can express Ig receptors that bind to pathogens on infected cells.

• Natural Killer T cells (NKT):

  • Share characteristics with both NK and T cells.

  • Have a TCR and are CD4+, but their TCR recognizes only lipids and glycolipids presented by CD1 (MHC-like molecules).

  • Have surface antibodies in addition to specific NK receptors.

  • Activated NKT cells secrete granules that kill target cells and can release cytokines to amplify or diminish the immune response.

Microscopic Analysis Methods

• Photon Microscopy: Uses specific stains like Hematoxylin and Eosin for cell visualization.

• Fluorescence Microscopy: Uses Immuno-Fluorescent (IF) labeling to identify and localize molecular content in cells.

• Flow Cytometry: Allows for analysis and quantification of intracellular (cytoplasm) and extracellular (surface) content.

CD Markers (Cluster of Differentiation)

CD markers are used to distinguish functional lymphocyte subpopulations. Some common examples include:

Chapter 2: Development of Lymphocytes

T Cell Development

T cell development is a complex process occurring in the thymus, involving several stages of selection to ensure proper function and self-tolerance.

Thymocyte Stages

1. Double Negative (DN) Thymocytes:

   • Do not express CD4 or CD8 markers.

   • Divided into four groups (DN-1 to DN-4) based on surface markers:

     	Genotype	Location	Description
     DN1	c-kit (CD117), CD44, CD25	Bone marrow to thymus	Migration to thymus
     DN2	c-kit (CD117), CD44, CD25	Subcapsular cortex	TCR, IL and chain rearrangement; T-cell lineage commitment
     DN3	c-kit (CD117), CD44, CD25	Subcapsular cortex	Expression of pre-TCR; selection
     DN4	c-kit (CD117), CD44, CD25	Subcapsular cortex to cortex	Proliferation, allelic exclusion of -chain locus; α-chain locus rearrangement begins; becomes DP thymocyte

2. β-Selection:

   • Process to identify cells that have successfully arranged their TCR-αβ.

   • Involves the formation of a pre-T-α chain, which is a precursor of the pre-TCR.

   • The pre-TCR initiates a signal transduction cascade, leading to several events, including the arrest of β chain rearrangement (allelic exclusion).

3. Double Positive (DP) Thymocytes:

   • Express both CD4 and CD8 markers (immature).

   • Constitute 80% of cells in the thymic cortex.

   • Express the complete TCR-αβ/CD3 complex, making them targets for selection.

   • Selection modulates their TCR repertoire by confronting them with MHC-peptides in the thymic cortex.

T Cell Selection Processes

Mature T cells must recognize only foreign antigens presented by self-MHC. This is achieved through two selection processes:

1. Positive Selection (Self-Restriction):

   • Favors thymocytes with TCRs capable of recognizing self-MHC presented antigens with an intermediate affinity.

   • This ensures that T cells will only react to antigens presented by the host's MHC molecules. Experiments involving "thymus chimeras" have shown that the thymus determines the MHC restriction of developing T cells.

2. Negative Selection (Self-Tolerance):

   • Eliminates thymocytes that have a high affinity for self-antigens, preventing auto-reactivity.

   • Occurs through clonal deletion: high-affinity interactions with TCR trigger apoptotic signals.

   • Medullary thymic epithelial cells (mTEC), which express AIRE, play a crucial role by presenting a wide array of self-antigens.

The Selection Paradox and Explanatory Models

The paradox is that positive selection promotes reactivity while negative selection eliminates it. Two models address this:

1. Affinity Model: States that differences in TCR signal strength determine the selection outcome.

   • Weak TCR signal: Positive selection.

   • Strong TCR signal: Negative selection.

   • No TCR signal: Apoptosis (death by neglect).

2. Altered Peptide Model (Phillipe Marrack and John Kappler):

   • Proposes that cortical thymic epithelial cells (cTEC) present different peptides than mTEC.

   • cTEC express unique thymoproteasomes and process peptides differently, inducing positive selection. Thymocytes positively selected there are spared from negative selection upon migration to the medulla.

Lineage Commitment (CD4+ or CD8+)

After selection, DP thymocytes choose to become either CD4+ or CD8+.

• This involves changes in gene organization and expression.

  1. Inhibition of one of the genes controlling CD4 or CD8 expression.

  2. Expression of genes associated with the specific function of the chosen lineage ( or CTL).

• Models for lineage commitment:

  • Instructive Model: The strength and duration of the TCR signal dictate the lineage.

    • Strong affinity for MHC I favors CD8+ development.

    • High affinity for MHC II and TCR/CD4 co-engagement drives CD4+ development.

  • Stochastic Model: A DP thymocyte randomly down-regulates CD4, leading to CD8 upregulation. However, signal interruption suggests an "interrupted signal model," where continuous TCR engagement leads to CD4+ and interrupted signals lead to CD8+.

• Transcription factors involved in regulating CD4/CD8 lineage choice:

  • ThPOK: Favors CD4+ development and inhibits RunX3.

  • RunX3: Favors CD8+ development and inhibits ThPOK.

Other T Cell Developments in the Thymus

• NKT (CD4+): Play a role in innate immunity; have an invariant TCR-α (iNKT) that interacts with CD1 to present glycolipids.

• Treg (CD4+): Inhibit acquired immune responses.

• Intraepithelial Lymphocytes (IEL): CD8+ cells involved in innate immunity, monitoring mucosal surfaces.

Thymus Exit and Maturation

After lineage commitment, thymocytes become quiescent and exit the thymus. Their migration depends on the expression of specific receptors.

Other Mechanisms of Self-Tolerance

Thymic negative selection is not always perfect. The body uses additional mechanisms to prevent autoimmunity:

• Regulatory T cells (Treg): Develop in the thymus and peripheral organs. They suppress other T cell development and auto-reactivity.

  • Medical implications of Treg suppression:

    • Depleting Treg cells before vaccination may increase vaccine efficacy.

    • Increasing Treg suppressive activity could treat allergies, autoimmune diseases, and prevent organ rejection.

    • Eliminating certain T cells can inhibit responses to some tumors.

• Apoptosis: Programmed cell death.

  • An energy-dependent process where cells self-destruct, unlike necrosis (cell death by injury or cytotoxicity).

  • In the thymus, apoptosis refines the T cell repertoire and regulates immune cell homeostasis.

  • Induced by stimuli activating Caspases (initiator and effector caspases).

  • Two pathways:

    • Intrinsic Pathway: Initiated in mitochondria by stimuli like radiation, stress, or growth factor withdrawal.

    • Extrinsic Pathway: Initiated by the binding of Fas to its ligand (Fas-L) on the surface of T cells.

B Cell Development

While not fully elucidated, many intermediates of B cell development have been identified.

Location of Development: Bone Marrow

• General Scheme: Involves generation of Common Lymphoid Progenitors (CLPs), B phenotype choice, B cell tolerance induction, and maturation.

• Development is guided by stromal cells of the bone marrow.

  • Stromal cells use adhesion molecules to retain HSCs and CLPs in specific niches, providing necessary molecular signals for differentiation.

  • They secrete cytokines that precisely dictate the migration and development of B cells.

Characteristics at Different Stages

• Surface Molecules: Antigens, adhesion molecules, cytokine receptors (e.g., CXCL12 on pre-pro-B cells, IL-7 on pro-B cells).

• Transcription Factors: Determine active genes at each developmental stage.

• Immunoglobulin Gene Rearrangement: Status of H and L chain gene rearrangement.

B Cell Selection for Self-Reactivity

Once a functional BCR is expressed on immature B cells, it is tested for reactivity to self-antigens.

Auto-reactive B cells may undergo one of three fates:

1. Clonal Deletion: Apoptosis.

2. Reactivation of Rag1/2 genes: To re-edit the light chain.

3. Escape Selection: Become anergic (inactive).

B cell negative selection is less stringent than T cell selection because B cells often require T cell help for activation and do not have an AIRE equivalent.

Maturation in the Spleen

Immature B cells, upon leaving the bone marrow, go through transitional stages (T1, T2) in the spleen before becoming mature B-2 cells.

• Immature B cells have a short half-life due to low anti-apoptotic molecules (Bcl-2) and high Fas expression.

• Most T1 cells develop into T2 in the spleen. T2 cells circulate to blood, lymph nodes, and spleen follicles.

B1 Cells and Marginal Zone B Cells

• B1 cells: Specialized in immune responses against pathogens in the blood.

Chapter 3: Major Histocompatibility Complex (MHC) and Antigen Presentation

The Major Histocompatibility Complex (MHC) is crucial for the immune system's ability to recognize and respond to antigens.

Antigen Recognition by Lymphocytes

• B cells: Possess antibodies (BCRs) on their surface that directly recognize intact antigens.

• T cells: Receptors (TCRs) recognize only processed fragments of antigens, presented by Antigen-Presenting Cells (APCs) on MHC molecules.

  • MHC molecules are encoded by a set of genes ("MHC Locus") with several heritable alleles.

  • MHC gene expression influences susceptibility to autoimmune diseases.

  • Antigen fragments are generated intracellularly by digestion into peptides, which form complexes with MHC molecules on the cell surface.

Histocompatibility and Organ Transplantation

• MHC molecules determine if an organ transplant between two individuals will be tolerated or rejected.

• Nobel laureates Benacerraf, Dausset, and Snell (1980) identified MHC functions in organ transplantation and immune response.

• Zinkernagel and Doherty showed MHC's role in acquired immunity, demonstrating T cell recognition of MHCs.

• Structural studies by Don Wiley confirmed the existence of diverse MHC molecules presenting different peptides.

Classes of MHC Molecules

There are two primary types of MHC molecules, MHC Class I and MHC Class II, structurally similar but differing in specific ways:

1. MHC Class I (MHC I):

   • Present on the surface of all nucleated cells.

   • Specialized in presenting intracellular antigens (e.g., viral proteins from the cytosol).

   • MHC I complexes are presented to CD8+ T lymphocytes (CTLs), which recognize and kill cells expressing intracellular antigens.

   • The peptide-binding groove has 8 antiparallel β-sheets and can accommodate peptides of 8-10 amino acids (AAs). α3 domain is highly conserved and interacts with CTL surface molecules.

   • The groove is blocked at both ends.

2. MHC Class II (MHC II):

   • Almost exclusively expressed on the surface of professional Antigen-Presenting Cells (APCs).

   • Specialized in presenting extracellular antigens absorbed by APCs (e.g., fungi, extracellular bacteria).

   • MHC II presents peptides from proteolyzed antigens to CD4+ T lymphocytes (), activating them to stimulate immune responses against extracellular antigens.

   • The peptide-binding groove has 8 antiparallel β-sheets and can accommodate peptides of 13-18 AAs.

   • The groove is open at both ends, allowing longer peptides to extend beyond the cavity.

MHC-Peptide Binding Characteristics

• MHC I and MHC II molecules show polymorphism in their peptide-binding region.

• Humans express only 6 classes of MHC I and 12 of MHC II, but this limited number can present a high number of peptide variants.

• MHC molecules are "promiscuous": each MHC molecule can bind several different peptides, and some peptides can bind different MHC molecules.

• MHC-peptide association is very stable ( to ).

• MHC I binding requires specific N- and C-terminal AAs (anchor residues) for anchoring the peptide.

• MHC II peptides (13-18 AAs) contain 7-10 aromatic or hydrophobic AAs in the middle and C-terminal region as major contact points. The flexibility allows for promiscuous binding.

MHC I Peptide Properties

• Peptides isolated from MHC I typically have 8-10 AAs (often 9 AAs).

• They possess key AAs in specific positions (anchor residues) that form hydrogen bonds with MHC I.

• The peptide undergoes torsion to fit the cavity, with extremities anchored and the middle prominent for T cell interaction.

MHC Gene Organization

• MHC is encoded by a gene cluster on chromosome 6 in humans (called HLA - Human Leukocyte Antigen) and chromosome 17 in mice (called H-2 complex).

• These genes encode three classes of molecules:

  • MHC Class I: Glycoproteins on all nucleated cells, presenting endogenous peptides to CD8+.

  • MHC Class II: Glycoproteins on APCs, presenting exogenous peptides to CD4+.

  • MHC Class III: Genes encoding proteins distinct from MHC I and II, some with immune functions (complement system, inflammation).

MHC Genetics and Inheritance

• Polymorphism: MHC genes are highly polymorphic, with many alternative alleles in a population.

• Haplotypes: MHC genes are closely linked and inherited as haplotypes. An individual inherits one haplotype from each parent.

• Codominance: Both parental haplotypes are expressed simultaneously in the same cells. Heterozygous individuals express products from both alleles.

• Recombination: Cross-over recombination in HLA is rare but contributes to locus diversity, creating new allelic combinations over generations. This makes identical HLA types rare between unrelated individuals, complicating transplants.

• Polygeneity: The MHC region is polygenic, containing genes with similar functions but different structures.

Functions of MHC Molecules

• Presenting self-molecules to indicate a healthy cell.

• Presenting peptides in MHC I to signal an infected cell and engage CTLs.

• Presenting self-peptides in MHC I and II to test T cell development for auto-reactivity.

• Presenting self-peptides in MHC I and II to maintain tolerance to self-proteins.

• Presenting foreign peptides in MHC I and II to signal infection and activate .

MHC Expression and Regulation

• MHC I expression: Present in all nucleated cells, but levels vary (high on lymphocytes, low/undetectable on fibroblasts, muscle cells, hepatocytes, some neurons). Constitutive expression is important because NK cells target cells lacking MHC. Erythrocytes do not express MHC I but avoid NK cell killing through CD47 expression.

• MHC II expression: Primarily on professional APCs (DCs, macrophages, B lymphocytes). Activation of APCs by antigens or cytokines increases MHC II expression.

Factors Affecting MHC Expression

• Genetic Regulation: Depends on promoters and transcription factors of MHC I and II genes (e.g., cIITA, RFX, "Bare Lymphocytes Syndrome").

• Viral Interference: Viral proteins can interfere with MHC synthesis or transport.

• Cytokine Signaling: IFN-α, β, and γ increase MHC expression. Corticosteroids and prostaglandins can decrease MHC II expression.

• MHC II Alleles (Haplotype): Influence the type of immune response and peptide selection.

MHC and Antigen Processing

Antigen processing is necessary for effective presentation (Ziegler K. and Unanue E. R. 1980).

• Internalized Exogenous Antigens: Are processed in the cytoplasm and presented on MHC II by APCs. This can be blocked by inhibitors of endoplasmic transport.

• Endogenous Antigens: Are processed in the cytosol and presented on MHC I. Requires living infected cells and protein synthesis.

Endogenous Pathway (MHC I)

• Proteins have a half-life, are degraded and recycled. Some polypeptides remain to be presented on the cell surface.

• The exact choice of peptides presented is still unclear.

Exogenous Pathway (MHC II)

• Antigens are internalized into endosomes (early pH 6-6.5, late pH 4.5-5) and lysosomes (pH 4.5).

• The invariant chain (Ii) guides MHC II to endosomes and prevents premature peptide binding. In the endosomes, Ii is degraded, leaving CLIP (Class II-Associated Invariant Chain Peptide).

• HLA-DM (non-classical MHC II) facilitates the exchange of CLIP for antigenic peptides.

Cross-Presentation and Non-Peptidic Antigens

Cross-Presentation

A mechanism where APCs (especially DCs) present exogenous antigens on MHC I to activate CD8+ T cells, which would normally only recognize endogenous antigens.

• Addresses two questions:

  1. How does the immune system activate naive CD8+ cells against intracellular antigens if the infected cell is not a professional APC?

  2. How can a professional APC present viruses from an extracellular source to activate CTLs if it's not infected itself?

• In cross-presentation, externally acquired antigens are directed to the MHC I presentation pathway.

• Mechanisms are still being studied, but it involves DCs licensed by CD4+ T cells. Activated CD4+ T cells provide co-stimulatory signals (like IL-2) to DCs, enabling them to cross-present.

Non-Peptidic Antigens

• Recognized by T cells, e.g., mycolic acid from Mycobacterium Tuberculosis.

• Presented by the CD1 molecule, a non-classical MHC I family member. CD1 structurally resembles MHC I but functionally shares similarities with MHC II.

Chapter 4: Infectious Diseases and Vaccination

Infectious diseases have driven immunology's development, and vaccination is a crucial tool for prevention.

Introduction to Infectious Diseases

• Vaccination has greatly reduced mortality from diseases like diphtheria, measles, polio, and tetanus.

• Challenges remain for diseases like HIV and Hepatitis C.

• Organizations like the WHO and CDC monitor health, conduct research, and provide public health guidelines.

Barriers to Infection

Physical and chemical barriers form the first line of defense:

1. Epithelial cells: In skin and digestive tract.

   • Low pH in the stomach and upper intestine.

   • Secretion of antibacterial peptides.

   • Normal gut flora inhibits pathogens through competition.

2. Intermediary host barriers.

Innate Immune Response to Pathogens

When barriers are breached, the innate immune response is often pathogen-specific:

• Bacteria: Endotoxins stimulate macrophages to secrete cytokines.

• Viruses: Induce interferon production, inhibiting viral replication and activating NK cells.

Viral Infections

Viruses are non-living entities composed of nucleic acids encased in a protein capsid (enveloped or non-enveloped).

• Viral lifecycle: Penetrates cells via specific receptors, releases genome for replication, produces new virions, which are then released to infect other cells.

• Viruses balance keeping the host cell alive for survival with killing it for propagation.

Viral Evolution and Evasion

• Mutant viruses: Arise from replication cycles, often adapted to hosts and resistant to immune detection.

• Some mutations increase virulence, creating lethal variants.

Viral Immune Evasion Mechanisms

• Hepatitis C virus: Inhibits protein kinase PKR.

• Herpes simplex virus: Inhibits TAP protein production (VP22).

• Measles and HIV: Reduce MHC II expression in infected cells.

• Vaccinia virus: Secretes a protein that inhibits complement molecules.

• HIV, EBV, CMV: Directly attack immune cells, causing immunosuppression.

• Influenza and HIV: High genetic variability to evade the immune system.

Influenza Virus

• The Spanish Flu (1918-1919) caused 20-50 million deaths.

• The influenza virus infects various species (humans, horses, birds, pigs, seals).

• Three types (A, B, C) based on matrix and nucleocapsid proteins. Type A has 13 H and 9 N subtypes.

• Genetic variation occurs via:

  • Antigenic Drift: Gradual, spontaneous point mutations leading to minor changes in H and N. Requires annual vaccine updates.

  • Antigenic Shift: Sudden emergence of a new, highly divergent strain (e.g., avian or swine flu), causing severe epidemics.

Bacterial Infections

• Entry: Through mucous surfaces (respiratory, urogenital, gastrointestinal) or skin lesions.

• Low inoculum leads to localized immune response (phagocytosis).

• High inoculum leads to specific immune response.

• Symptoms often due to immune response against the pathogen, not the pathogen itself.

• Bacterial pathogenesis: Often causes local inflammation due to toxin secretion.

  • Endotoxins: Constituent molecules (e.g., LPS of bacterial cell wall).

  • Exotoxins: Secreted molecules.

• Immune response:

  • Extracellular bacteria: Humoral response.

  • Intracellular bacteria: Cellular response (IFN-γ activates macrophages and NK cells).

Tuberculosis (Mycobacterium tuberculosis)

• Pulmonary infection transmitted via respiratory droplets.

• Bacilli are ingested by alveolar macrophages and proliferate by inhibiting phagolysosomes.

• Immune response: CD4+ mediated. 2-6 weeks post-infection, CD4+ cells secrete IFN-γ, leading to activated macrophage infiltration.

• Healing leaves visible scars on X-rays.

• CD4+ mediated response often protects against reinfection but 10% develop chronic pulmonary or extrapulmonary TB.

• Treatment requires long antibiotic courses (9 months).

• An effective vaccine (BCG) exists for non-pulmonary TB (attenuated Calmette-Guérin bacillus strain).

Parasitic Infections

Parasites are either protozoa (unicellular eukaryotes) or helminths (multicellular worms).

• Examples: Malaria, sleeping sickness, leishmaniasis, toxoplasmosis.

• Vectors: Often arthropods (flies, mosquitoes, ticks). Eliminating vectors helps stop disease spread.

• Immune response depends on location:

  • Extracellular: Humoral response.

  • Intracellular: Cellular response.

Malaria (Plasmodium falciparum)

• Symptoms: Fever, chills, episodic sweating, anemia, weakness, headaches, renal/cardiac failure, cerebral malaria. Symptoms are due to excessive cytokine production (e.g., INF-α).

• Immune response is often poor in endemic regions; young children have high mortality.

• Challenges for immunity: Parasite variability, intracellular phase, drug resistance.

Fungal Infections (Mycoses)

• Around 400 of a million fungal species are pathogenic to humans.

• Immune defense:

  • Innate immunity: First defense. Commensal organisms limit growth. Neutrophil phagocytosis is effective.

  • Recognition via PAMPs (e.g., β-glucans, mannans, chitin) and PPRs (e.g., Toll-like receptors, CR3).

  • Evasion by capsule production against PRRs.

  • Acquired immunity: Involves antibody production.

Emerging and Re-emerging Infections

• Emergence:

  • High population density in poor regions and cities.

  • Increased air travel.

  • Import of infected food.

  • Excessive antibiotic use.

  • Climate change.

  • Human encroachment on wildlife habitats.

• Re-emergence:

  • Tuberculosis: Immunodeficiency, excessive antibiotic use.

  • Diphtheria: Interruption of vaccination programs (e.g., Russia).

  • Vaccine rejection by religious groups.

Vaccination and Immunization

• Vaccination: Intentional exposure to non-pathogenic forms of pathogens.

• Immunization: Process leading to a definitive state of protective immunity.

Types of Immunization

1. Passive Immunization: Direct transfer of antibodies; transient, no memory cells generated.

   • Antibody transfer to fetus via placenta.

   • Antiserum injection for immunodeficiency, toxins/venom, or highly virulent pathogen exposure.

2. Active Immunization: Induces immunization and memory cells; definitive, leads to a secondary response.

   • Naturally, by infection.

   • Artificially, by vaccine administration.

Vaccine Requirements and Development

• Requirements: Safe, effective, low cost, targets desired immune response (cellular or humoral), targets infection site (e.g., mucosa), provides long-lasting protection (memory).

• Development process: Long and costly.

  1. Animal testing: Rodents, non-human primates.

  2. Human clinical trials:

     1. Phase I: Safety (side effects).

     2. Phase II: Efficacy in inducing immune response.

     3. Phase III: Testing in large target population.

Key Takeaways

• The immune system is a sophisticated network of cells and organs safeguarding the body.

• Hematopoietic Stem Cells (HSCs) are the ultimate source of all immune cells, with their development and differentiation precisely controlled.

• Primary lymphoid organs (bone marrow, thymus) are crucial for lymphocyte development, while secondary lymphoid organs (lymph nodes, spleen, MALT) are where immune responses are initiated.

• T cell development in the thymus involves rigorous positive and negative selection processes to ensure self-MHC restriction and self-tolerance.

• B cell development in the bone marrow undergoes selection to prevent auto-reactivity, with maturation completed in peripheral organs like the spleen.

• The Major Histocompatibility Complex (MHC) is central to T cell antigen recognition, presenting processed peptides via MHC I (intracellular antigens to CD8+ T cells) and MHC II (extracellular antigens to CD4+ T cells).

• Cross-presentation is an important mechanism for DCs to present exogenous antigens on MHC I, thereby activating CD8+ T cells against pathogens that evade direct infection of APCs.

• Infectious diseases, caused by viruses, bacteria, parasites, and fungi, pose significant global health challenges, but are combated by diverse immune responses.

• Vaccination is a highly effective and cost-efficient public health intervention, designed to induce protective immunity and memory against specific pathogens.

• Understanding the mechanisms of immune evasion by pathogens is critical for developing new treatments and vaccines.