see also:

• innate immunity
• immunology
• autoimmune disease

• adaptive immunity refers to the ability to specifically target pathogens based upon past exposure to that pathogen
• in contrast, innate immunity is a relatively non-specific immunity system although pentraxin 3 (PTX3) does play a similar role as antibodies but they are not adaptive to new pathogens
• HLA proteins specific to an individual can bind to specific intracellular or extracellular foreign antigens and present them to lymphocytes resulting in either cell death and/or stimulation of B lymphocytes to produce antibodies which will provide additional future, more rapid detection of the antigen and earlier immune response.

• see also: https://en.wikipedia.org/wiki/Human_leukocyte_antigen
• these intracellular molecules are able to “detect” certain intracellular protein fragments from a pathogen inside the cell and then present them to the cell surface. If immune cells recognize these fragments as not being self proteins, the immune cells become activated and destroy the “infected” cell
• gene complexes found mainly on chromosome 6
• these MHC class I proteins associate with β2-microglobulin, which, unlike the HLA proteins, is encoded by a gene on chromosome 15
• HLA class I:
  • present antigens (8-14 amino acid long peptides derived from the endoplasmic reticulum lumen) from INSIDE ANY cell to CD8+ cytotoxic T cells
  • are expressed in nearly all cells
  • heterodimers consisting of an alpha heavy chain (anchored in the cell membrane) and a light chain (beta-2 microglobulin)
  • polymorphisms within exon 2 and exon 3 are responsible for the peptide binding specificity of each class one molecule
  • β2-microglobulin (B2M) is a critical component of the MHC class I molecule and is required to present tumor antigens to T cells. Its loss in some cancer cells results in acquired resistance to immune checkpoint blockade (ICB) therapies.¹⁾
  • HLA-A gene:
    • the alpha chain ranked among the genes with the fastest-evolving coding sequence in humans with well over 7,000 known alleles
    • lymphocyte bound CD8 binds to residues 223-229 in the α3 domain of HLA-A
    • HIV virus is able to down-regulate the expression of HLA-A by binding to the cytoplasmic tail of the Class I MHC while it is still in the endoplasmic reticulum preventing it from migrating to the cell surface (HIV via it's negative regulatory factor (Nef) enables HIV to also downregulate CD4 and CD8 on T cells)
  • HLA-B gene:
    • HLA-B27
  • HLA-C gene:
• HLA class II:
  • present antigens from OUTSIDE of the cell to CD4+ T-lymphocytes via antigen presenting cells
  • there are two parts to each HLA class II molecule: an alpha part and a beta part. They, in turn, come from three different groups of genes: DR, DP, and DQ. The DR group has one primary gene, DRB1, and three other genes, DRB3, DRB4, and DRB5. The DP and DQ groups have two genes, DPA and DPB and DQA and DQB.
    • major MHC class II proteins only occur on antigen-presenting cells, B cells, and T cells:
      • HLA-DP
      • HLA-DQ
      • HLA-DR
    • other MHC class II proteins, DM and DO, are used in the internal processing of antigens, loading the antigenic peptides generated from pathogens onto the HLA molecules of antigen-presenting cell.
  • the alpha and beta parts can come from the same gene or different chromosomes.
  • in 2023, 50,000 molecules of the HLA class II were mapped ²⁾

• CD4+ effector T cells promote the inflammatory response
  • activated by HLA class II bound antigens on the surface of “infected” cells
  • activated T cells release many substances including:
    • interferon-γ which has a range of actions such as:
      • stimulation of macrophages to synthesize and release neopterin (this can be used as a biomarker of cellular immune response activity and as this precedes antibody response, it can be a “universal” biomarker and urine or serum levels are proportionate to disease severity and rises with viral and bacterial infections, allograft rejection, sarcoidosis and immune disorders)
    • interleukin-2 (IL-2)
    • soluble form of the interleukin-2 receptor (sIL-2R) - the soluble form of the interleukin-2 receptor which can be used as a biomarker
  • stimulate antibody-producing B-cells to produce antibodies to that specific antigen
  • are remarkably effective in controlling melanoma via multiple helper and effector modes ³⁾
• regulatory Treg cells suppress the inflammatory response
  • inhibit the activation of effector T-cells
  • express cytotoxic T-lymphocyte-associated protein 4 (CTLA-4)
  • are important in inducing mucosal tolerance, as they mute the immune response to benign foreign antigens and, as a master transcription factor, express forkhead box P3 (Foxp3)
  • exist in tissues throughout the body, however, their frequency is much higher in the colon
    • colonization by commensal microbiota appears to facilitate the development of colonic Treg cells that express transcription factor RAR-related orphan receptor γ (RORγt)
      • commensal bacteria lead to Treg cell development through different mechanisms, including the use of polyunsaturated fatty acid (PUFA) as a substrate to produce lipophilic metabolites which lead to Treg cell development:
        • all-trans retinoic acid (atRA)
        • 9,10-dihydroxy-12Z-octadecenoic acid (9,10-DiHOME) - may indirectly induce Treg cells through functional modifications of dendritic cells (DCs) - activation of PPARγ in DCs was seen to upregulate Aldh1a2, thereby promoting Treg differentiation ⁴⁾
  • Co-expression of Foxp3 with BCL6 thymic derived Tregs (aka follicular regulatory T (Tfr) cells)
    • repress B cells and repress B cell differentiation to plasma cells (PCs) and suppress the formation of autoantibodies typically found in systemic autoimmune diseases, as well as allergen-specific IgE
    • Tfr cells dampen B cell antibody responses in part through expression of CTLA-4
    • prevent the emergence of autoantibodies and excessive IgE via production of neuritin which is taken up by B cells, causes phosphorylation of numerous proteins, and dampens IgE class switching ⁵⁾
  • Co-expression of Foxp3 with Tbet thymic derived Tregs
    • repress Th1 cells
• TH1 CD4+ T helper cells
  • play a crucial role in the immune system by promoting the cellular immune response, particularly against intracellular pathogens such as viruses and certain bacteria
  • activate macrophages through the secretion of cytokines like interferon-gamma (IFN-γ), enhancing their ability to destroy infected or cancerous cells.
  • help in the development and activation of cytotoxic T cells (CD8+), which can directly kill infected cells
  • produce other pro-inflammatory cytokines like IL-2 and TNF-α, contributing to a strong cell-mediated immune response
  • essential for combating intracellular infections and regulating the balance of immune responses during various diseases and infections and can oppose TH2 activity to reduce inflammation (eg. in ulcerative colitis)
  • are implicated in certain autoimmune disorders when dysregulated, due to their role in driving inflammation
  • markers for TH1 cells include surface proteins (CCR5, CXCR3) and transcription factors (T-bet, STAT1, STAT4), which guide their differentiation and function
• TH2 CD4+ T helper cells
  • activation and function rely on prior antigen exposure and specificity
  • differentiate in response to specific antigens presented by antigen-presenting cells
  • essential for orchestrating adaptive immune responses, especially through secretion of cytokines like IL-4, IL-5, and IL-13, which aid the defense against helminths and contribute to allergic reactions and auto-immune diseases
  • the gene Malat1 is a critical player in regulating immune responses in female TH2 cells, but not in males. Malat1 regulates female Th2 cell cytokine expression through controlling early differentiation and response to IL-2. This genetic difference may partly explain why women have a higher prevalence of auto-immune diseases⁶⁾ (perhaps along with post-pregnancy chimeric stem cells from foetus which may persist for decades)
• CD8+ cytotoxic killer T-cells
  • respond to cells with HLA class I bound antigens presented on the surface of antigen presenting cells
  • it seems dietary trans-vaccenic acid (from milk, lamb or beef) reprograms CD8+ T cells and improves anti-tumour immunity ⁷⁾
  • it seems a diet deficient in indoles (from cruciferous vegetables like broccoli, maternal milk if mother has indoles in diet) impairs the AHR system and a reduced population of intestinal CD8+ T cells and reduced immunity to Cryptosporidium infection in childhood ⁸⁾
  • the dietary carotenoid zeaxanthin directly enhances the activity of CD8+ T cells by stabilizing and strengthens the formation of TCR complex on CD8+ T cells upon interacting with the cancer cells ⁹⁾
• CD4+ and CD8+ T cells play a crucial role in clearing Covid-19 viral infection in the nasal cavity via the secretion of Granzyme B, a cytotoxic molecule but do not seem to do this in the lungs ¹⁰⁾

• produce immunoglobulin type antibodies

• the aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that is activated by small molecules provided by the diet, microorganisms, metabolism and pollutants
• AhR is expressed by a number of immune cells, and thus, AhR signaling provides a molecular pathway that integrates the effects of the environment and metabolism on the immune response
• it is a member of the Pern-Arnt-Sim (PAS) superfamily of transcription factors that are involved in sensing environmental signals such as changes in the circadian rhythm (BMAL1 and BMAL2), oxygen tension or redox potential (HIF-1α, HIF-2α, HIF-3α) among others ¹¹⁾
• in response to activation by a ligand, AhR translocates from the cytoplasm to the nucleus where it controls the transcription of a wide variety of target genes
• it is the mediator of the toxic effects of dioxins
• it is activated by dietary indoles which thus may protect children from Cryptosporidium infections ¹²⁾

• invertebrates
  • some have developed their own adaptive immunity systems based
  • Down’s syndrome cell-associated molecule (DSCAM) in insects and crustaceans, in which a single gene generates thousands of variant isoforms by alternative splicing
  • insect and crustacean DSCAM variants are also expressed in cells involved in immunity, including haemocytes and the fat body, and are secreted into the haemolymph
  • DSCAM molecule contains eight immunoglobulin V domains arranged in an S-shape, and the variability clusters into two sites in the structure, one that specifies homophilic (and limited heterodimeric) pairing and one that may contribute to specific antigen binding.
• jawless invertebrates
  • developed their own adaptive immunity systems
  • many different leucine-rich repeats (LRRs), as are found in Toll-like receptors (TLRs)] were discovered and named variable lymphocyte receptors (VLRs)
  • Analysis of genomic DNA revealed a few VLR genes in the haploid genome to which LRR sequences are added by a copy choice mechanism from LRR pseudogenes, resulting in upwards of 10^14 different sequences with evidence for both allelic exclusion and clonal expression
  • The resulting proteins can be anchored in the cell membrane by glycolipid linkage, or may be secreted as pentamers of dimers. These pentamers have low affinity but high avidity for antigen.
  • Two kinds of VLR genes were found, VLR-A and VLR-B, for which monoclonal antibodies (mAbs) defined two kinds of lymphocytes with different distributions in lamprey tissues. Both kinds of lymphocytes respond to antigens; VLR-B cells bind antigen and secrete VLRs, while VLR-A cells do not but instead respond to a phytohaemagglutinin, a T-cell mitogen.
  • Overall, the data suggest that the VLR-A lymphocytes may be like T cells and the VLR-B lymphocytes like B cells, leading immediately to the question of whether lymphocytes specialized into functionally different subsets independently in jawless fish and jawed vertebrates, or only once, after which different receptor molecules evolved (or persisted) in jawless fish and in the jawed vertebrates.
• jawed invertebrates including humans
  • adaptive immunity evolved based upon antibodies (Abs), T-cell receptors (TCRs) and major histocompatibility complex (MHC) molecules with T cells being produced by a thymus gland
  • the key event occurred at the base of the jawed vertebrates some 500 million years ago: the creation of the first split V gene from the insertion of a transposon into the immunoglobulin V exon of what is presumed to have been a membrane-bound receptor, which used recombination-activating genes (RAGs) to specify imprecise joining of the different parts of the split V gene. It has been argued that this first receptor was a TCR-like molecule, based on the fact that diversity is generated by recombinational joining only at complementarity-determining region 3 (CDR3), which is the major contact with peptide in MHC molecules. In this view, αβ T cells emerged first, followed by γδ T cells and then by B cells. The first MHC molecule was probably a class II-like homodimer, the gene for which duplicated and diverged to create a heterodimer, from which the first class I heavy chain and β2-microglobulin genes could be generated by an inversion.¹³⁾
  • Many if not most non-mammalian vertebrates share the salient features first found in the chicken MHC, with MHC genes located close to polymorphic antigen-processing genes to allow co-evolution as stable haplotypes
  • Two rounds of genome-wide duplication at the base of the vertebrates led to MHC paralogous regions, including the CD1 region and arguably the regions containing natural killer (NK) receptor genes in humans. The primordial MHC was the birthplace of the adaptive immune system, which has been breaking apart ever since.
  • A crucial property for an adaptive immune system with variable antigen-specific receptors is self-tolerance, part of which occurs in the thymus during development of T cells.
    • a chemokine system was identified for homing of thymic lymphoid precursors: zebrafish chemokine (C-C motif) ligand 25 (CCL25) (equivalent to human tyrosine kinase expressed in hepatocellular carcinoma) and zebrafish chemokine (C-X-C motif) ligand 12 (CXCL12) (equivalent to human CXCR12, or stromal cell derived factor 1). Both these genes were found throughout the jawed vertebrates, but only the equivalent of CCL25 was found in the jawless fish lamprey (Lampetra planeri), which lacks an obvious thymus, and neither was found in the protochordate amphioxis (Branchiostoma floridae), which lacks lymphocytes altogether.
  • the evidence suggests that vertebrate hosts evolved with strong selective pressure from parasites, leading to some individuals with an immune response that protects from parasites but leads to pathological responses (eg. asthma, auto-immune conditions) in the absence of parasites.
    • the importance of an antibody receptor called FcγRIIB in the balance between susceptibility to systemic lupus erythromatosis (SLE) and protection from malaria. FcγRIIB locus explains 25% of the genetic variation in SLE. SNPs in FcγRIIB genes can also be important, with the I232T mutation in the transmembrane region abolishing function. The population distribution of T232 world-wide correlates both with susceptibility to SLE and with the geographic distribution of malaria, and the frequency of severe malaria in T232 homozygotes is half that of heterozygotes or I232 homozygotes. The balance between the inhibitory FcγRIIB molecule and the activatory FcγRIIIB molecule determines, at least in part, the immune response, with less inhibition apparently driven by the advantage of increased survival from malaria.¹⁴⁾
• role of CD33
  • CD33 is a receptor on immune cells binds to a type of sugar called sialic acid that all human cells are coated with and when bound it “recognises” the other cell and does not attack
  • gonococcus also coats itself with sialic acid which helps it escape immune attack
  • humans have picked up a new version of the CD33 which differs to that in chimpanzees and this version is missing the sugar-binding site and perhaps makes our immune system more effective against gonococcus
    • in addition, this mutated version no longer prevents microglia in the CNS to break down damaged cells and plaques and thus may have a role in reducing dementia in humans

• T cells develop in the thymus, which is largest at birth and during the first years of life.
  • Mature single CD4+ and CD8+ positive T cells are first detected in the thymus at week 15 and abundant in the periphery well before birth, however, neonatal T cells differ significantly from adult cells, reflecting the fetal life, where exposure to foreign antigens is largely restricted to non-inherited maternal alloantigens and thus they actively promote self-tolerance and are anti-inflammatory.
  • Foreign antigen activation of late fetal or neonatal T cells results in a response skewed towards Th2 immunity, which is reinforced by neonatal dendritic cells and epigenetic features.
  • At birth, nearly all T cells carry the CD45RA glycoprotein, typical of naive T cells, which have never encountered foreign antigen
  • Very early-life adaptive T-cell immunity is thus characterized by tolerogeneic reactivity, reduced allo-antigen recognition and poor responses to foreign antigens.¹⁵⁾
• Two types of B cell arise via distinct developmental pathways: ¹⁶⁾
  • B1 cells spontaneously secrete low-affinity IgM with a limited range of antigen specificities (including common bacterial polysaccharides), have fewer somatic mutations and serve as a first line of defence. B1 cells secrete IL-10 and TGF-β, and thus promote a Th2 response. At birth, B1 cells comprise 40% of peripheral blood B cells and this frequency remains high for a few months.
  • Conventional B cells (designated B2 cells) originate from a multi-linage CD34+ common lymphoid progenitor and generate a broad repertoire of immunoglobulin specificities due to their expression of terminal deoxynucleotidyl transferase, which enhances diversity in V-D-J immunoglobulin gene segment joining.
  • B cells are typically present in secondary lymphoid organs and in the bone marrow, where they contribute to the humoral response of the adaptive immune system.
  • IgG has a half life of 29 days and so its production must be maintained and this is achieved by the antibody-producing plasma cells that develop during an immune response migrating to the bone marrow, where they are very long lived. In addition, there may be continuous regeneration of memory B cells in contact with persisting antigen and helper T cells - particulate antigens persist for years in lymph nodes, held by follicular dendritic cells. Antigen persistence and cross-reactive antigens probably help to keep these B cells alive ¹⁷⁾
  • the immune system keeps many chronic infections under control and asymptomatic (eg. CMV, EBV, TB) but these may become symptomatic or lethal if the immune system is suppressed.
• Most antibody responses are dependent on T-cell help.
  • They rely on interactions between the TCR and the engagement of co-receptors including CD28 and CD40 ligand on Th2 or follicular T helper cells with their corresponding binding partners HLA-peptide, CD80/86 and CD40 on antigen-specific B cells.
  • neonatal B cells express low levels of these co-receptors, limiting their capacity to respond - critical early protection against many infectious diseases previously experienced by the mother is given by the passive IgG antibody transferred from the mother transplacentally and in milk. Mothers who escaped childhood infection via herd immunity actually place their own children at higher risk as they are unable to provide passive immunity.
  • young children become more vulnerable to infections once the maternal IgG levels reduce, though are becoming better armed with the maturing innate and adaptive immune systems. Repeated exposures to pathogens results in accumulation of immunological memory as an evolving feature of the adaptive immune response which provides protection often well into old age.
• 20% of all lymphocytes reside in the gut
  • gut bacteria influence the development of Th17 cells, Treg cells and memory T cells
  • Segmented filamentous bacteria in the gut are necessary for the development of Th17 cells and Clostridium spp. induce colonic Treg cells
  • it would appear that the microbiome shapes the development of both memory T and B cells
  • The carbohydrate antigens of the ABO blood groups cross-react with gut bacterial antigens and stimulate IgM antibody responses.
  • intraepithelial lymphocytes (IELs):
    • most IELs that originate in the small intestine, cecum, and colon were T-cells, whereas only a minor proportion of stomach-derived IELs were T-cells ¹⁸⁾
    • T-cell IELs (T-IELs)
      • “constantly survey the epithelium of the GI tract to sense commensal microorganisms and signs of infection through T-cell receptors (TCR) or other receptors that help maintain GI tract barrier integrity”
      • “are critical in the communication network between the gut epithelium, microbiome, and diet”
      • “IELs play a crucial role in defense against colon cancer”
      • “are either thymic-derived, such as γδ and αβ T-cells, or induced, which develop from peripheral CD4+/CD8+ αβ T-cells” ¹⁹⁾
• the immune response to the same stimulus varies between adults considerably due to:
  • the great complexity of the T- and B-cell repertoires including that due to past exposures and cross-reactivites
  • a large stochastic element in choosing which cells will respond to a given stimulus
  • somatic mutations in B cells
  • degree of immunocompetency eg. immunosuppressive medications, diabetes, age, etc
    • immune senescence predisposes older adults to a higher risk of acute viral and bacterial infections
    • the mortality rates of these infections are generally three times higher among elderly patients compared with younger adult patients
    • infectious diseases are still the fourth most common cause of death among the elderly in the developed world
    • the ageing immune system fails to maintain full tolerance to self-antigens, with an increased incidence of autoimmune diseases
    • the innate immune response also declines with age and is also associated with chronic inflammatory states with increase in pro-inflammatory cytokines IL-1β, IL-6, IL-18 and TNFα
    • aberrant immune responses in the aged can exacerbate inflammation, possibly contributing to other scourges of old age: cancer, cardiovascular disease, stroke, Alzheimer's disease and dementia ²⁰⁾
  • considerable genetic variability in how individuals respond, determined by:
    • the highly polymorphic HLA genes
    • the genes of innate immunity
    • ABO blood group
  • see also this 2023 study on the human population variation in single-cell responses to SARS-CoV-2 ²¹⁾
    • the scientists identified around 1,200 human genes whose expression in response to SARS-CoV-2 is under the control of human genetic factors and the frequency of the alleles that regulate these genes can vary between the populations studied
    • population variation in immune responses is driven largely by cellular heterogeneity, but genetic variants with marked allele frequency variation contribute to population differences at specific loci
    • individual's prior infection exposures:
      • variations in latent CMV - CMV antibdies vary greatly across populations: Central Africans present 99% seropositivity, in contrast to only 50% in East Asians and 32% in Europeans
        • whilst latent cytomegalovirus (CMV) infection alters lymphoid cellular proportions in the immune system, they found CMV⁺ had a limited direct effect on SARS-CoV-2 responses, with only one gene presenting significant expression differences in response to this virus
    • past natural selection
      • pathogen-imposed selection pressures have been paramount during human evolution and selection has impacted present immune responses to SARS-CoV-2, particularly in people of East Asian ancestry, in whom coronaviruses generated strong selective pressures around 25,000 years ago when it is proposed timing of an epidemic that affected the evolution of host coronavirus-interacting proteins
      • the rs1142888-G allele
        • they found a greater than 2.8-fold higher levels of GBP7 expression in response to viral stimulation in Europeans compared with in Africans has a higher frequency of this allele in Europe probably results from selection occurring 21,900–35,600 years ago.
        • GBP7 facilitates IAV replication by suppressing innate immunity, but also regulates host defence to intracellular bacteria such as Listeria monocytogenes and Mycobacterium tuberculosis, providing a plausible mechanism for positive selection at this locus
      • variants of IRF1, IFNAR2 and DR1 associated with lower COVID-19 severity increase type I IFN signalling in lymphoid cells by upregulating IRF1 and IFNAR2 or downregulating DR1, attesting to the importance of efficient IFN signalling for a favourable clinical outcome
      • degree of Neanderthal genome
        • 1.5% and 2% of the genomes of Europeans and Asians is of Neanderthal origin
        • there is growing evidence of links between Neanderthal ancestry and present-day immunity to infection
        • by comparing the 1,200 genes identified with the Neanderthal genome, the scientists have discovered dozens of genes that both alter antiviral mechanisms and result from ancient introgression between Neanderthals and modern humans
        • there appears to be a link between Neanderthal haplotypes and COVID-19 severity
        • MUC20 (mucin-related gene)
          • a Neanderthal-introgressed eQTL increases MUC20 expression in SARS-CoV-2-stimulated CD4+ T cells and decreases COVID-19 susceptibility