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 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.

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 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.

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.

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.

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.

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.

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.

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.

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.

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.

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.