Evolution of the Immune System

Innate Immune System Evolution

• Every living organism, from bacteria to humans, possesses an innate immune system for defense against external and internal aggressions.
• Adaptive immune systems, capable of producing antibodies and cytotoxic killer cells, are present only in a small fraction of living organisms.

Phagocytosis

• Phagocytosis is a key mechanism, especially in the innate immune system.
• Epithelial cells, part of the body, have multiple functions: nutrient uptake, waste excretion, physical barrier, mucus secretion/resorption, pH maintenance.
• Epithelial cells secrete antimicrobial molecules and peptides, including reactive oxygen species. However, they are fixed and non-mobile.
• Leukocytes are mobile cells that patrol in the blood or reside in tissues.

Simple Organisms (e.g., C. Elegans)

• These organisms have only epithelial cells and no circulating blood.
• Their defense strategy focuses on avoiding infections rather than fighting them.
• They deposit melanin and produce antimicrobial proteins and pattern recognition receptors (PRRs).

Flies

• Flies possess a haemolymph (equivalent to circulating blood), a partial Toll-like receptor (TLR) system, and a fat body (equivalent to the liver).
• They produce antimicrobial peptides and have leukocytes:
  • Plasmatocytes (phagocytic cells).
  • Crystal cells (deposit melanin and trigger clotting).
  • Lamellocytes (encapsulate pathogens, similar to granuloma formation in mammals).
• The TLR system was first discovered in Drosophila melanogaster (fruit fly).
• Bruce Beutler, Jules Hoffmann, and Ralf Steinmann discovered TLR4 as the LPS receptor.

Phagocytic Cells

• Phagocytes engulf inert or infective particles; phagocytosis means "to eat" (phagos) by a cell (cytos).
• They are found even in primitive multicellular organisms like sponges.
• Phagocytes discriminate between self and non-self molecules and perform effector functions.
• Eli Metchnikoff discovered phagocytosis as a crucial element in defense while studying primitive organisms. He initially was an embryologist and he reasoned that feeding needs are really driving the defence mechanisms.
• Metchnikoff's theory took years to be accepted.
• Phagocytes constantly perform surveillance and possess PRRs and complement receptors.
• They contain phagosomes and autophagosomes and produce antimicrobial peptides, reactive oxygen species, and reactive nitrogen species.
• Granulocytes (neutrophils, eosinophils, and basophils) have granules that fuse with phagosomes or are exocytosed to attack pathogens.
• Neutrophils undergo NETosis, releasing neutrophil extracellular traps (NETs) made of DNA and antimicrobial peptides to kill bacteria even after the neutrophil's death.

Jawed Vertebrates

• They have a common innate immune system and specialized cells.
• Innate cells interact with the adaptive immune system via antigen-presenting cells.
• Development of granulocytes (neutrophils, basophils, eosinophils) and mononuclear cells (monocytes, macrophages, dendritic cells) occurs.
• Birds have heterophils, similar to neutrophils but with different granules and enzymes; also found in rabbits, turtles, and opossums.
• Mononuclear phagocytes originate from myeloid progenitors and include monocytes, macrophages, and dendritic cells.
• These cells produce cytokines and chemokines and present antigens.

Adaptive Immune System Evolution

• The "immunological big bang" refers to the rapid development of the adaptive immune system.
• Occurred approximately 450-500 million years ago, parallel with the development of jaws.
• Development of cells from lymphoid progenitors: T cells, B cells, and innate lymphoid cells (ILCs), including NK cells (ILC1), ILC2, and ILC3.
• Specialized organs like the thymus and spleen developed; lymph nodes are a feature of mammals.
• T cells and B cells can pick up antigen, mature and express effector molecules.
• Key immune molecules include immunoglobulins (B cell receptors), T cell receptors, and MHC molecules.

Molecular Basis of Immune Recognition

• Based on immunoglobulin superfamily (IGSF) domains, made of two beta pleated sheets with specific bonds, found in immunoglobulins and adhesion molecules (e.g., ICAM-1, VCAM-1).
• Variable domains pick up specific ligands.
• Recombination activating genes (RAGs) are crucial for the immunological big bang.
• T cells and B cells generate a vast variety of antigen receptors via DNA segment rearrangement.
• RAGs evolved from a transposon and act as recombinases, catalyzing DNA recombination to underpin diversity of recognition.
• B and T cells undergo random rearrangement of V, D, and J segments to encode the variable region of immunoglobulins or T cell receptors.

T Cell Receptors

• Complementarity determining regions (CDRs) are key.
• Do not undergo somatic hypermutation or class switching.

B Cell Receptors

• Have an antibody structure with a variable region and a constant region attached to the cell membrane.
• Activation-induced deaminase (AID) mediates somatic hypermutation and class switching in lymph nodes.
• Camel antibodies have only one chain.
• Class switching requires both AID and lymph nodes.
• The types of immunoglobulins that have been described and identified include IgM, IgD, IgA, IgG, and IgE.

Control Mechanisms and Immune Tolerance

• Issue of control arises due to the potential to produce antibodies to almost anything.
• Concept of self versus non-self recognition is linked to autoimmunity.
• Paul Ehrlich introduced the concept of Hor autotoxicos (horror of self-toxicity).
• Frank Macfarlane Burnett proposed the clonal selection theory.
• Mechanisms to maintain unresponsiveness include sequestration and active regulatory mechanisms (immune tolerance or immune anergy).
• Autoimmunity is not necessarily autoimmune disease; autoimmune disease develops when regulatory mechanisms of immune tolerance break down.
• Clonal selection, not clonal deletion, is key.

Transition Species (e.g., Lamprey)

• Possess a spine but no jaw.
• Have some but not all molecules, cells, and organs of the adaptive immune system.
• Exhibit pseudo-adaptive immune mechanisms and AID but lack major histocompatibility complex (MHC) molecules.

Holobionts

• Every organism is a holobiont, comprising its own genes and the genes of symbiotic organisms.
• A real ecological unit with the organism composed of its own cells and genes, and commensal pathogens.
• Phenotypes evolve in time and space due to microbe colonization.
• Holobiont includes the host genome, microbiome (lungs, gut, skin), and environmental metagenome.
• Engineering commensal bacteria (e.g., Staphylococcus epidermidis) in the skin's microbiome to express vaccine antigens (linked to accumulation associated protein, AAP) can enhance antibody production.

Summary

• Phagocytes are the basic element in immunology.
• Macrophages and dendritic cells collaborate with T cells to present antigens.
• Partnerships exist between mast cells, eosinophils/basophils (expressing IgE receptors), and B cells.
• Evolution is not linear; there are weird examples.
• Antibody diversity is larger than the diversity of the T cell receptor.
• Transition species like lampreys exist.
• We are all holobionts; evolution affects the microbes that colonize us.