Comparative Immunology Flashcards

Comparative Immunology: An Overview

Introduction

• Comparative immunology investigates major differences in the immune system between different organisms.
• Focuses on variation in immune mechanisms, aspects not observed in humans, evolution of the immune system, and development of model systems.
• Marsupials and monotremes are key taxa due to their unique phylogenetic positions and millions of years of independent evolution.

Marsupials and Monotremes

• Mammals diverged into prototherians (egg-laying) and therians (live birth) about 165 million years ago.
• Marsupials branched off from eutherians (placentals) approximately 154 million years ago.
• These groups have extant representatives, enabling comparative studies on their immune systems despite vast evolutionary distances.
• Ideal for comparative immunology due to their evolutionary divergence, allowing for understanding and potential exploitation of immune system differences.

Areas of Comparison

• Anatomical: Lymphoid tissue structure (bone marrow, spleen, lymph nodes, mucosal-associated lymphoid tissue).
• Functional: Immune cell populations, activation processes, presence or absence of specific cell types.
• Molecular: Immunogenetics.

Anatomical Comparisons: Thymus

• Early studies (1900s) found similar lymphoid tissue structure and complexity in marsupials, monotremes, and humans, but noted key differences in the thymus and timing of immune development.
• Location Differences:
  • Eutherians and polyprotodont marsupials (e.g., opossums) have the thymus in the thorax.
  • Diprotodont marsupials (e.g., wallabies) have two thymus locations: cervical and thoracic.
  • The thymus is the site of T cell (T lymphocyte) maturation; B cells mature in the bone marrow.
• Functionality:
  • The thymus is fully functional at birth in eutherians.
  • Functionality in marsupials is not well-characterized, believed to be not fully functional at birth.
  • The thymus involutes with age, becoming smaller and changing function.
• Young animals have a thymus full of naive cells, some activated and memory cells, and thymic epithelial cells.
• As animals age, naive cells convert to activated or memory cells, and thymic epithelial tissue decreases.

Timing of Immune Development

• Timing differs significantly between marsupials, eutherians, and monotremes.
• Marsupials have short gestation periods (e.g., 30 days), are immunologically naive at birth, and enter non-sterile environments (the pouch).
• Eutherians have longer gestation, are born at a late developmental stage, are immunocompetent, and develop in a sterile uterine environment.
• In marsupials, the liver is the hematopoietic tissue at birth (bone marrow in humans);
• They lack a mature immune system at birth.
• Lymphoid structures and maturation develop over months.

Protection in Marsupials

• Passive immunity via milk (antibodies) from the mother.
• Two-stage antibody protection in the pouch:
  • Initially, milk contains more IgA and transferrin.
  • Later, a switch occurs with different antibodies in the milk to protect against different pathogens.
• Antimicrobial peptides in the pouch, transferred to pouch young, target and kill bacteria and fungi.
  • Opossums have 12 antimicrobial peptides; Tasmanian devils have 7+.

Understanding Marsupial and Monotreme Immunity

• Early beliefs assumed marsupials and monotremes had primitive immune responses based on conflicting reports of delayed antibody responses and lack of lymphocyte response.
• Advances in molecular technology (DNA sequencing) revealed complex immune systems with cytokines, lymphocytes, and similar functionality to humans.
• Experiments on mast cells showed their immune system is comparable to eutherians.

Immune Cell Populations

• Marsupials and monotremes possess a complete repertoire of immune cell populations:
  • CD4 lymphocytes (helper T cells that coordinate, activate, and direct other immune cells) and CD8 lymphocytes (cytotoxic T cells that kill infected cells).
• Initial difficulties in identifying these cells were due to a lack of specific markers and inability of human antibodies to bind to marsupial cells.
• The external coding of their cells is different due to evolutionary distance.

Functional Similarities and Differences

• Overall, marsupials and monotremes are functionally more similar to eutherians.
• They have similar tissue and cell types, antibody production, and immune cell activation and memory.
• The level and way they respond differ between species.
• For example, platypus and marsupial mouse responses to stimuli vary.

Immunogenetics: Molecular Differences

• Most recent understanding comes from sequencing genomes and studying evolution of the mammalian immune system.
• Many marsupials and monotremes lack fully sequenced genomes (opportunistic sampling, rare species).
• Sequencing reveals the number, type, and expression of receptors, antibody production, signaling molecules (cytokines), and immune system activation and development.
• The first marsupial genome sequence was the opossum in 2007; the short-beaked echidna genome was completed in 2021.

T Cell Receptors (TCRs)

• TCRs on the surface of T cells present antigens to MHC II, activating the immune response.
• Four conserved TCR chains (alpha, beta, delta, and gamma) exist across jawed vertebrates, forming heterodimers.
• Marsupials and monotremes have a fifth unique chain, developed before their divergence 165 million years ago.
• This chain has two isoforms, with only one found in monotremes.

Toll-Like Receptors (TLRs)

• TLRs are expressed on immune and non-immune cells, recognizing and binding to pathogen-associated molecular patterns.
• They activate both the innate (generic, first-line defense) and adaptive (specific antigen response) immune systems.
• They have the same repertoire of TLRs as eutherians, except TLR1 and TLR6 are combined as one unit, TLR1/6.
• In monotremes and marsupials, TLR1 and TLR6 were not duplicated and evolved separately, remaining a combined unit from an ancestral gene.

Major Histocompatibility Complex (MHC)

• MHC is used to identify major differences between marsupial and monotreme species.
• Classes I and II are involved in antigen presentation.
• This is the most variable region of the genome, thus likely to reveal variations between species.
• The number and complexity of MHC genes are similar in monotremes, marsupials, and eutherians.
• However, they possess unique genes, and their genomic clustering differs (e.g., MHC gene class I UT is only found in marsupials and monotremes).
• The arrangement of MHC genes differs; in opossums (marsupials), class I and II regions are both sitting on one region and not interspersed as they are in human and mice genomes..

Immunoglobulins (Antibodies)

• Immunoglobulins consist of two heavy and two light chains.
• Eutherians and monotremes have five classes (IgA, IgG, IgM, IgD, IgE).
• Marsupials lack IgD and have single subtypes of IgA and IgG.
• Diversity in the variable region (antigen-binding site) is important to allow different antigen binding, so as to increase the range of antigens they are protected from.
• Eutherians have high diversity in heavy and light chains.
• Marsupials and echidnas have limited heavy chain diversity but maximum light chain diversity.
• Platypuses have limited diversity in both heavy and light chains.

Research Implications

• Understanding differences in immune anatomy, function, and development is crucial for vaccine development and disease modeling.
• Mice and sheep have significant differences in immune cell populations.
• Vaccines need to target specific immune cell populations.
• Pathogens are host-specific, meaning they behave differently in different animals.

Doom and Gloom Story

• A vaccine against an intracellular bacterial disease in cattle and sheep was developed using mutated bacterial cells.
• The vaccine protected mice, but did not prevent infection or shedding in goats.
  ### The immune system in mice and sheep, goats, or cow, are very different.

Important Lessons

• The immune system differs significantly between species.
• Understanding these differences is crucial to avoid issues in research and development.
• Consider using appropriate models (e.g., sheep cells, in vitro sheep infection model) instead of relying solely on mouse models.

Lecture Overview

• The marsupial and monotreme immune system is generally similar to, instead of primitive as initially believed, eutherians.
• There are key differences in anatomical, functional, and molecular aspects:
  • Anatomical: Thymus and timing of immune development differ.
  • Functional: Similar to eutherians functionally, but limited data.
  • Molecular: Unique molecular immune parameters (TCR chains, TLRs, MHC organization).
• Importance of comparative immunology lies in highlighting variation in immune mechanisms, understanding ancestors, and informing model selection for biomedical/veterinary research.