Comparative Immunology Notes

Comparative Immunology

Introduction

• Comparative immunology investigates major differences in the immune system between different organisms, typically those distantly related.
• Focuses on variation in immune mechanisms to understand aspects not observed in humans, benefit to other animals, and develop model systems.
• Examines the evolution of the immune system using taxa with interesting positions on the phylogenetic tree, such as marsupials and monotremes.

Marsupials and Monotremes

• Marsupials and monotremes are valuable for comparative immunology due to their unique position on the mammalian evolutionary tree and their continued existence today.
• Prototherian mammals (monotremes) lay eggs, diverging from therian mammals (live birth) about 165 million years ago.
• Marsupials, characterized by pouch young, branched off from eutherians (placentals) approximately 154 million years ago.
• The significant evolutionary distance (up to 165 million years) between monotremes, marsupials, and eutherians makes them ideal for comparative studies to understand and potentially exploit immune system differences.

Areas of Comparison

• Anatomical: Focuses on lymphoid tissue (development and immune response sites).
• Functional: Studies immune cell populations, their activation, and presence/absence.
• Molecular: Investigates immunogenetics using techniques like DNA sequencing.

Anatomical Comparisons: Thymus

• Early studies (1900s) on marsupials and monotremes revealed similar lymphoid tissue structure and complexity compared to humans, but noted key differences in the thymus and timing of immune development.
• Eutherians and polyprotodont marsupials (multiple lower incisors, e.g., opossums) have the thymus located in the thorax.
• Diprotodont marsupials (two lower incisors, e.g., wallabies) have two thymus locations: cervical and thoracic regions.
• The thymus is essential for T cell maturation; T cells in the thymus and B cells in the bone marrow.
• In eutherians, the thymus is fully functional at birth, whereas in marsupials, it is believed to be not fully functional or only partially functional.
• The thymus involutes with age, becoming smaller and changing function as naive cells convert to activated or memory immune cells, and thymic epithelial tissue reduces.

Timing of Immune Development

• The timing of immune development differs greatly between marsupials and Eutherian mammals and especially then between marsupials and monotremes.
• Marsupials have short gestations (e.g., 30 days), are immunologically naive at birth, and enter a non-sterile pouch environment.
• Eutherians' gestation is longer (e.g., nine months), born at a late developmental stage, are immunocompetent, and develop in a sterile uterine environment.
• In marsupials, the liver functions as hematopoietic tissue at birth (bone marrow in humans), and they lack a mature immune system at birth.
• Marsupials receive passive immunity via milk containing IgA and transferrin and have antimicrobial peptides in the pouch that target bacteria and fungi.
• Antimicrobial peptides are found in the pouch and milk, expressed in the skin of pouch young, include: human (1), opossums (12), and Tasmanian devils (7+).

Functional Immunology

• Early beliefs that marsupials and monotremes had a primitive immune response, partly due to conflicting reports of delayed or dampened antibody responses, have been overturned.
• Recent advances, especially in molecular technology (DNA sequencing), show that marsupials and monotremes possess complex immune systems comparable to humans, with cytokines, lymphocytes, and functional immune cell populations (CD4 and CD8 lymphocytes).
• The lack of specific markers initially hindered the identification of immune cell populations in these animals, requiring the development of new antibodies.
• Marsupials and monotremes are functionally more similar to eutherians, with similar tissue and cell types, antibody production, and immune cell activation and memory, although the level and manner of response can differ.
• For example, when comparing a platypus to a marsupial mouse, different stimulus levels evoke various immune marker responses.

Molecular Immunology

• Immunogenetics, particularly genome sequencing, provides insight into the evolution of the mammalian immune system.
• Genome sequencing of marsupials and monotremes is challenging due to their rarity, endangerment, and difficulty in obtaining suitable samples.
• Genome sequencing allows investigating the number, type, and expression of receptors, antibody production, use of signaling molecules (cytokines), and the activation and development of their immune systems.
• As of 2007, the opossum was the first marsupial to have its genome sequenced, and in 2021, the short-beaked echidna genome was completed.
• Across all jawed vertebrates, four T cell receptor (TCR) chains (alpha, beta, delta, gamma) are conserved, forming heterodimers, that present antigens to MHC II to activate an immune response.
• Marsupials and monotremes have these conserved chains plus a fifth chain unique to them, indicating it developed before their divergence ~165 million years ago and was subsequently lost in eutherians.
• Toll-like receptors (TLRs) are expressed on immune and non-immune cells, binding to pathogen-associated molecular patterns (PAMPs) and activating both innate and adaptive immune systems.
• Innate immunity is the first line of defense, broad, generic response. Adaptive immunity is a specific response to a specific antigen.
• Marsupials and monotremes have a similar repertoire of TLRs to eutherians, except TLR1 and TLR6 are combined.
• Major histocompatibility complex (MHC) is variable in the genome and used to identify differences between marsupial and monotreme species
• MHC has three classes, two of which (MHC I and MHC II) are involved in antigen presentation. The number and complexity of MHC genes are similar to eutherians, but they also have unique genes and gene clustering is different.
• The MHC gene class one UT is only found in marsupials and monotremes; is highly duplicated, and ancient.
• Immunoglobulins (antibodies) have two heavy and two light chains. Eutherians and monotremes have five classes (IgA, G, M, D, and E). Marsupials lack IgD and have a single IgA and IgG subtype.
• Diversity within the variable region of antigen recognition is important. Eutherians have high diversity in both heavy and light chains. Marsupials and echidnas have limited heavy chain diversity, and maximum light chain diversity.

Research Implications

• Understanding the differences in immune anatomy, function, and development is important for vaccine development, as vaccines target specific immune cell populations.
• Pathogens can be host-specific, and disease models in one species may not accurately represent the disease in another.
• In an overview of vaccine development, a vaccine developed from mutated bacterial cells worked for mice, but didn't for goats.
• The selection of the appropriate model is an important consideration in research.

Summary

• Marsupial and monotreme immune systems are generally similar to eutherians but have key differences.
• Anatomical: Thymus location and timing of immune system development.
• Functional: Generally similar to eutherians; however, there's more functional characteristics that are still left unknown.
• Molecular: Quite unique in coding and function; there are unique molecules in molecular immune space.
• Comparative immunology highlights variation in immune mechanisms.