The immune system is a network of cells, tissues*, and organs that work together to defend the body against attacks by “foreign” invaders. These are primarily. Immune system (IS) a complex network of specialized cells, cell products, tissues and molecules and their interactions incurred during the phylogenetic. confirms its importance in survival.1 Adaptive immunity is the hallmark of the immune system of higher animals. This response consists of antigen-specific.
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PDF | The immune system in a broad sense is a mechanism that allows a living organism to discriminate between "self" and "non-self. PDF | All organisms are connected in a complex web of relationships. the potential of our sophisticated immune system in the service of human health. The immune system has evolved to protect the host from a universe of pathogenic microbes that are themselves constantly evolving. The immune system also.
These signals trigger B-cell division, class switching of the antibody genes and somatic hypermutation. B cells that express mutated antibody that binds immunogen with higher affinity are then favoured. Selection for better binding antibodies continues over months, ultimately resulting in high-affinity antibody coming from highly mutated germ line genes.
High-affinity antibodies are more effective at neutralizing or opsonizing invading microbes and their pathogenic products. The somatic hypermutation process does not occur in T cells, even though they have antibody-like T-cell receptor genes, because there is no advantage in having a high-affinity T-cell receptor.
The T-cell receptor binding to the peptide—HLA complex on an antigen presenting cells has low affinity. It is enhanced by several co-receptor—ligand pairs that are not antigen-specific, giving the T cell the signal to divide and function.
As the individual gets older, he or she develops an expanding repertoire comprising memory T and B cells triggered by previous infections and vaccinations, but also a naive-memory repertoire shaped by exposure to the microbiome, food antigens and inhaled antigens. Given the great complexity of the T- and B-cell repertoires and a large stochastic element in choosing which cells will respond to a given stimulus, and somatic mutations in B cells, the precise composition will differ in each individual, even in monozygotic twins [ 66 ].
Add to this considerable genetic variability in how individuals respond, determined by the highly polymorphic HLA genes [ 67 ] and by the genes of innate immunity, and it is not surprising that the immune responses of any single adult vary considerably.
It is beyond the scope of this review to explore the immunology of pregnancy in detail reviewed in [ 68 , 69 ]. However, successful reproduction is of central evolutionary importance and there are immunological issues.
How the newborn retains mechanisms by which the fetus minimizes its immune responses to the mother has been discussed above. A bigger puzzle is how the mother tolerates a semi-allogeneic graft without rejecting it and without the immunosuppression necessary to accept an organ transplant [ 70 ]. There are features at the trophoblast maternal interface at the site of initial implantation and in the placenta that subvert the normal graft rejection immune response.
These include expression only of non-polymorphic non-classical HLA antigens on the trophoblast [ 71 ], local immune suppression mediated by infiltrating NK cells [ 72 ], monocytes and T regulatory cells [ 69 , 73 ], and inhibition of T-cell activation by tryptophan catabolism [ 74 ].
Around the time of implantation, a local inflammatory response sets up the stable placental site [ 68 ].
There is evidence that the mother changes the balance of her T-cell responses to Th2 rather than Th1 [ 68 ]. Thus pregnant women can show remissions of autoimmune disease [ 75 ], and are more susceptible to severe complications of influenza [ 76 ] and some other infections. This immune modulation, necessary for the well-being of the fetus, can occasionally be harmful to the mother. The primary role of the immune system is probably to protect against infections.
Other roles such as destruction of mutated cells may be very important, though more so in old age after reproduction. However, the side effects of such therapy and of the passive transfer of anti-cancer T cells include autoimmune reactions, suggesting a balance between anti-self-immune reactions preventing cancer and causing autoimmunity [ 79 ].
The fading immune system in old age see below may ameliorate autoimmunity but at the expense of increased cancer risk. Microorganisms cause about a quarter of all cancers e. Specific T-cell responses normally hold these microbes in check. However, if immunity is impaired through ageing see below , immunosuppressive therapy or certain infections, particularly HIV-1, these cancers emerge [ 80 ].
Therefore, having developed a fully effective immune response in early childhood, this matures as memory accumulates and maintains the health of the individual during critical periods of life, including child bearing. It not only protects against potentially lethal infections but also controls a number of persisting infections, some of which have the potential to cause cancer. It can also deal with mutant cells that have potential for becoming malignant.
It can be over-reactive and cause autoimmune disease or allergy, a price paid for the overall benefit. That ends this strange eventful history,. As age advances, the immune system undergoes profound remodelling and decline, with major impact on health and survival [ 81 , 82 ]. This immune senescence predisposes older adults to a higher risk of acute viral and bacterial infections. Moreover, the mortality rates of these infections are three times higher among elderly patients compared with younger adult patients [ 83 ].
Infectious diseases are still the fourth most common cause of death among the elderly in the developed world. Furthermore, aberrant immune responses in the aged can exacerbate inflammation, possibly contributing to other scourges of old age: Furthermore, poor immune responses account for diminished efficacy of vaccines [ 82 , 85 ].
Immune senescence also results in reactivation of latent viruses, such as varicella-zoster virus, causing shingles and chronic neuralgia. Deterioration of the immune system with age may compromise the homeostatic equilibrium between microbiota and host. Thus reduced bacterial diversity in the gut has been correlated with Clostridium difficile -associated diarrhoea, a major complication for the elderly in hospitals [ 86 ].
Moreover, deviations from the intestinal microbiota profile, which was established in youth, are associated with inflammatory bowel disease [ 87 ]. The increase with age in pro-inflammatory pathobionts and the decrease in immune-modulatory species may promote and sustain inflammatory disorders [ 86 ]. At the same time, the ageing immune system fails to maintain full tolerance to self-antigens, with an increased incidence of autoimmune diseases.
This is probably due to lymphopaenia occurring with age, leading to excess homeostatic lymphocyte proliferation [ 89 ], as well as a decrease in regulatory T-cell function and decreased clearance of apoptotic cells by macrophages [ 81 ]. Cancer is most frequent in older people; the median age for cancer diagnosis in industrialized countries is approaching 70 years of age. The main reason is obviously the accumulation of cellular and genetic damage throughout life; however, given the role of the immune response in controlling cancers, reduced immune functions in the elderly must contribute to the higher risk [ 90 ].
This immune impairment is in apparent contradiction to the increase in autoimmunity as anti-tumour responses can be directed against self; however, the general decline of the immune system probably prevails and tumours are no longer rejected as efficiently. Moreover, the increased inflammation found with age facilitates cancer emergence. The increased morbidity due to the decline of the immune system is a direct consequence of dysregulated adaptive immunity in the elderly.
The low number of naive T cells versus T cells [ 41 , 42 ] is a consequence of the reduced thymic output from the involuted thymus. While peripheral B-cell numbers do not decline with age, the composition of this compartment changes. In general, the changes in the T- and B-cell compartments hamper the adequate immune response to new acute and latent viral infections and vaccinations.
The innate immune response also declines with age. There are changes in innate cell numbers, with skewing of haematopoiesis towards the myeloid lineages [ 93 , 94 ]. Similarly, ageing macrophages have a decreased respiratory burst. Indeed, when senescent cells were removed from aged mice artificially, the animals lived longer and were healthier [ 96 ]. The resulting low-grade inflammation probably contributes to atherosclerosis, dementia and cancer, inextricably linking inflammation and ageing of other tissues [ 84 , 98 ].
The cellular and molecular basis of immune senescence is still not well understood. Three phenotypes characterize senescent cells: While most of the data have been obtained in fibroblasts, senescent immune cells probably show similar features.
These features impact on mitotically active cells by depletion or arrested division e. Attrition of telomeres is a protective mechanism against cancer, as each round of proliferation is likely to introduce mutations [ ]. Only epithelial lymphocytes and stem cells including haemopoietic HSCs express the telomere-lengthening enzyme telomerase in the adult [ ], requiring a careful balance against the risk of cancer.
Both memory T cells and HSCs characteristically divide rarely, to minimize telomere attrition, but reliably either in response to infection memory lymphocytes or for tissue renewal stem cells throughout the entire lifespan. These cells accumulate in old age and in patients with autoimmune diseases and chronic viral infections [ ].
The second characteristic of aged cells is increased mitochondrial dysfunction and ensuing oxidative damage to proteins and DNA.
DC function in aged mice can be restored through administration of anti-oxidants [ ]. Oxidative stress causes DNA breaks and may be the cause of telomere attrition, which links the first two causes of ageing. The accumulation of oxidative damage could be due to a decline in lysosomal and autophagy function [ ].
Mice without autophagy in their haematopoietic system display a prematurely aged haematopoietic system [ ].
Failing memory T cells' responses to flu vaccination observed in the elderly can be restored with an autophagy-inducing compound [ ]. A third more recent addition to these fundamental changes of aged cells is the acquisition of the SASP, contributing to increased pro-inflammatory cytokine secretion and low-grade inflammation [ 99 ].
As a long-lived species, humans have evolved mechanisms of innate immunity and immunological memory to survive recurrent infections. However, over the lifetime of an individual, these immune mechanisms change, first to adapt to the change from fetus to infant, and then to mature and expand during growth, subtly changing in pregnancy and finally decreasing in senescence. The output of naive lymphoid cells and the ability to form new immunological memory becomes increasingly less important as the older individual will have encountered and established a memory bank to many pathogens over its lifetime.
There is a possibility that the myeloid bias and the increased secretion of pro-inflammatory cytokines during ageing are essential for improved phagocytosis of an increasing number of senescent cells, raising the question of whether the changes in the ageing immune system might serve a purpose. The immune system has been primarily moulded by evolution to respond efficiently to acute infections in young people, to adapt to pregnancy and to transmit protection to infants, and is adapted to cope with many chronic infections lasting for decades.
Apart from fighting viruses, bacteria, fungi and parasites, the immune system also assumes other roles such as tissue repair, wound healing, elimination of dead and cancer cells, and formation of the healthy gut microbiota. Assuming an absence of a major selective pressure on humans beyond reproductive age, we may have to pay for genetic traits selected to ensure early-life fitness by the later development of immunological phenotypes such as chronic inflammation.
Massive ageing and advanced longevity are very recent phenomena occurring in an optimized environment. As proposed by Hayflick [ ], ageing may be an artefact of civilization, and hence changes in the ageing immune system might just be a consequence of evolutionary unpredicted antigenic exposure over the lifetime of an individual.
In some aspects, the immune system of the aged organism resembles that of the newborn, with reduced antimicrobial activity by neutrophils and macrophages, reduced antigen presentation by DCs and decreased NK killing, and somewhat compromised adaptive lymphocyte responses. The evolution of the immune system within an individual possibly reflects the central role of the young adult in the survival of the species for its procreative potential. National Center for Biotechnology Information , U.
Journal List Proc Biol Sci v.
Proc Biol Sci. Katharina Simon , 1 Georg A. Hollander , 2 and Andrew McMichael 3. Katharina Simon. Georg A. Author information Article notes Copyright and License information Disclaimer. Invited to commemorate years of scientific publishing at the Royal Society. Received Jan 20; Accepted May 1. This article has been cited by other articles in PMC. Abstract This article reviews the development of the immune response through neonatal, infant and adult life, including pregnancy, ending with the decline in old age.
Introduction And one man in his time plays many parts, His acts being seven ages. William Shakespeare 1. Open in a separate window. Figure 1. From childhood to adulthood Then, the whining schoolboy with his satchel And shining morning face, creeping like snail Unwillingly to school. Evolution of the human immune system As a long-lived species, humans have evolved mechanisms of innate immunity and immunological memory to survive recurrent infections.
Acknowledgements We acknowledge Andrew Allen for preparation of the figure. Endnote 1 All epigraphs in this paper are from William Shakespeare's As you like it , act 2, scene 7. Competing interests We declare we have no competing interests. Funding A. References 1. Abbas AR, et al. Immune response in silico IRIS: Genes Immun. The influenza pandemic: Neutrophil and endothelial adhesive function during human fetal ontogeny.
Phagocytic ability of neutrophils and monocytes in neonates. BMC Pediatr. Forster-Waldl E, et al.
Monocyte toll-like receptor 4 expression and LPS-induced cytokine production increase during gestational aging. Role of MyD88 in diminished tumor necrosis factor alpha production by newborn mononuclear cells in response to lipopolysaccharide. Immaturity of infection control in preterm and term newborns is associated with impaired toll-like receptor signaling.
Human newborn polymorphonuclear neutrophils exhibit decreased levels of MyD88 and attenuated p38 phosphorylation in response to lipopolysaccharide. Lipopolysaccharide-induced tumor necrosis factor-alpha and IL production by lung macrophages from preterm and term neonates. Phenotype and function of neonatal DC.
Impaired responses to toll-like receptor 4 and toll-like receptor 3 ligands in human cord blood. Ontogeny of myeloid cells. Schuller SS, et al. Preterm neonates display altered plasmacytoid dendritic cell function and morphology. Neonatal natural killer cell function: Differentiation and functional regulation of human fetal NK cells. Off to a slow start: Immunobiology , — Haddad R, et al. This article has been cited by other articles in PMC.
GN, tolerance, renal transplantation, immunology, ARF. The Beginning of the Journey Imagine that you are a primitive animal, perhaps a distant predecessor of all mammals. Open in a separate window. Figure 1. Innate and Adaptive Immunity Devising a sophisticated biologic system, as evolution teaches us, does not require the destruction of preexisting, primitive tools, but instead depends on preserving and building on the best of them 3.
Figure 2. Linking Innate to Adaptive Immunity What good, however, are two immune systems in one body if they do not communicate with each other? Figure 3. Lymphoid Organs: A Brief Lesson in Geography Optimal and timely activation of the adaptive immune response, however, cannot possibly rely on chance encounters between T lymphocytes and the mature DCs that carry the antigenic peptides they recognize.
Blurring the Lines You have thus far conducted your work carefully, dividing the immune system into innate and adaptive and separating antigens along simple, clean lines into harmless self antigens on one side and harmful nonself microbes on the other.
The Immune System and the Kidney Pondering the relationship between the kidney and the immune system brings three medical inflictions immediately to mind: Figure 4. Autoimmune Renal Disease The kidney can be either the direct target of autoimmunity, whereby a T lymphocyte or antibody that binds a renal antigen elicits renal pathology, or the kidney can be a victim of collateral damage caused by a systemic immune response to self or nonself antigens.
Transplant Rejection Another price that your descendants will pay for the highly sophisticated but imperfect immune system you have bestowed upon them is the rejection of life-saving organ transplants. AKI A less anticipated and, until recently, overlooked function of the immune system is its role in tissue injury unrelated to infection—so-called sterile tissue injury. Epilogue It is not often that one biologic system touches so many aspects of human biology in both sickness and health.
Glossary Adaptive Immunity Adaptive immunity comprises defense mechanisms mediated by immune cells known as lymphocytes T, B, and natural killer cells and the specialized molecules required for their function. Antigen Antigen is a nonself molecule, usually a protein, that incites an adaptive immune response. Cytokines Cytokines are protein molecules produced by cells of the immune system that mediate diverse defensive functions.
Dendritic Cells DCs Dendritic cells DCs are a specialized myeloid cell that is induced by infection to take up antigens, process them into small peptides, package them inside major histocompatibility complex MHC molecules, and present them to T lymphocytes after migrating to secondary lymphoid organs. Innate Immunity Innate immunity comprises defense mechanisms mediated by the evolutionary more primitive components of our immune system.
Lymphocytes Lymphocytes are hematopoietic cells that mediate adaptive immunity. Secondary Lymphoid Organs Secondary lymphoid organs are organs or tissues where mature trained lymphocytes reside or circulate through.
Toll-Like Receptors TLRs Toll-like receptors TLRs are receptors expressed principally on innate immune cells but also present on adaptive immune cells and nonimmune cells. Disclosures None.
Acknowledgments F. Footnotes Published online ahead of print. References 1. Gordon S: Elie Metchnikoff: Father of natural immunity. Eur J Immunol Invertebrate Immunity , edited by Soderhall K, editor. Why study the evolution of immunity? Nat Immunol 8: Innate immune recognition. Annu Rev Immunol Trained immunity: A memory for innate host defense. Cell Host Microbe 9: Seeking the origins of adaptive immunity. Gearhart PJ: The birth of molecular immunology.
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Nat Rev Nephrol 9: The immune system and kidney disease: Basic concepts and clinical implications. Nat Rev Immunol Bluestone JA: Mechanisms of tolerance. Lakkis FG: Immunotherapy in Transplantation: Origin and biology of the allogeneic response. Cold Spring Harb Perspect Med 3: T cells and their eons-old obsession with MHC. Am J Transplant 9: Enzymes called granzymes are also stored in, and released from, the granules.
Granzymes enter target cells through the holes made by perforin. Once inside the target cell, they initiate a process known as programmed cell death or apoptosis, causing the target cell to die.
Another released cytotoxic factor is granulysin, which directly attacks the outer membrane of the target cell, destroying it by lysis. Cytotoxic cells also newly synthesise and release other proteins, called cytokines, after making contact with infected cells. Cytokines include interferon-g and tumour necrosis factor-a, and transfer a signal from the T cell to the infected, or other neighbouring cells, to enhance the killing mechanisms.
Via interferons Virally infected cells produce and release small proteins called interferons, which play a role in immune protection against viruses. Interferons prevent replication of viruses, by directly interfering with their ability to replicate within an infected cell.
They also act as signalling molecules that allow infected cells to warn nearby cells of a viral presence — this signal makes neighbouring cells increase the numbers of MHC class I molecules upon their surfaces, so that T cells surveying the area can identify and eliminate the viral infection as described above.
Via antibodies Viruses can also be removed from the body by antibodies before they get the chance to infect a cell.