Immune system

Immune system

title="Basophil granulocyte">basophils, and
  • Immune System – from the University of Hartford (high school/undergraduate level)
  • Microbiology and Immunology On-Line Textbook – from the University of South Carolina School of Medicine (undergraduate level)
  • Immunobiology; Fifth Edition – Online version of the textbook by Charles Janeway (Advanced undergraduate/graduate level)
  • Stanley Falkow's talk: "Host-Pathogen Interaction and Human Disease"

External links

  1. ^ a b c Beck, Gregory; Gail S. Habicht (November 1996). "Immunity and the Invertebrates" ( 
  2. ^ "Inflammatory Cells and Cancer", Lisa M. Coussens and Zena Werb, Journal of Experimental Medicine, March 19, 2001, vol. 193, no. 6, pages F23–26, Retrieved Aug 13, 2010
  3. ^ "Chronic Immune Activation and Inflammation as the Cause of Malignancy", K.J. O'Byrne and A.G. Dalgleish, British Journal of Cancer, August 2001, vol. 85, no. 4, pages 473–483, Retrieved Aug 13, 2010
  4. ^ Retief FP, Cilliers L (January 1998). "The epidemic of Athens, 430–426 BC". South African Medical Journal 88 (1): 50–3.  
  5. ^ Ostoya P (1954). "Maupertuis et la biologie". Revue d'histoire des sciences et de leurs applications 7 (1): 60–78.  
  6. ^ Plotkin SA (April 2005). "Vaccines: past, present and future". Nature Medicine 11 (4 Suppl): S5–11.  
  7. ^ The Nobel Prize in Physiology or Medicine 1905 Nobelprize.org Accessed 8 January 2009.
  8. ^ Major Walter Reed, Medical Corps, U.S. Army Walter Reed Army Medical Center. Accessed 8 January 2007.
  9. ^  
  10. ^ The Nobel Prize in Physiology or Medicine 1908 Nobelprize.org Accessed 8 January 2007
  11. ^ a b Litman GW, Cannon JP, Dishaw LJ (November 2005). "Reconstructing immune phylogeny: new perspectives". Nature Reviews Immunology 5 (11): 866–79.  
  12. ^ a b c Mayer, Gene (2006). "Immunology — Chapter One: Innate (non-specific) Immunity". Microbiology and Immunology On-Line Textbook. USC School of Medicine. Retrieved 1 January 2007. 
  13. ^ Smith A.D. (Ed) Oxford dictionary of biochemistry and molecular biology. (1997) Oxford University Press. ISBN 0-19-854768-4
  14. ^ a b c d e f g h i Alberts, Bruce; Alexander Johnson; Julian Lewis; Martin Raff; Keith Roberts; Peter Walters (2002). Molecular Biology of the Cell; Fourth Edition. New York and London: Garland Science.  
  15. ^ Medzhitov R (October 2007). "Recognition of microorganisms and activation of the immune response". Nature 449 (7164): 819–26.  
  16. ^ Matzinger P (April 2002). "The danger model: a renewed sense of self". Science 296 (5566): 301–5.  
  17. ^ Boyton RJ, Openshaw PJ (2002). "Pulmonary defences to acute respiratory infection". British Medical Bulletin 61 (1): 1–12.  
  18. ^ Agerberth B, Gudmundsson GH (2006). "Host antimicrobial defence peptides in human disease". Current Topics in Microbiology and Immunology. Current Topics in Microbiology and Immunology 306: 67–90.  
  19. ^ Moreau JM, Girgis DO, Hume EB, Dajcs JJ, Austin MS, O'Callaghan RJ (September 2001). "Phospholipase A(2) in rabbit tears: a host defense against Staphylococcus aureus". Investigative Ophthalmology & Visual Science 42 (10): 2347–54.  
  20. ^ Hankiewicz J, Swierczek E (December 1974). "Lysozyme in human body fluids". Clinica Chimica Acta 57 (3): 205–9.  
  21. ^ Fair WR, Couch J, Wehner N (February 1976). "Prostatic antibacterial factor. Identity and significance". Urology 7 (2): 169–77.  
  22. ^ Yenugu S, Hamil KG, Birse CE, Ruben SM, French FS, Hall SH (June 2003). "Antibacterial properties of the sperm-binding proteins and peptides of human epididymis 2 (HE2) family; salt sensitivity, structural dependence and their interaction with outer and cytoplasmic membranes of Escherichia coli". The Biochemical Journal 372 (Pt 2): 473–83.  
  23. ^ Gorbach SL (February 1990). "Lactic acid bacteria and human health". Annals of Medicine 22 (1): 37–41.  
  24. ^ Hill LV, Embil JA (February 1986). "Vaginitis: current microbiologic and clinical concepts". CMAJ 134 (4): 321–31.  
  25. ^ Reid G, Bruce AW (August 2003). "Urogenital infections in women: can probiotics help?". Postgraduate Medical Journal 79 (934): 428–32.  
  26. ^ Salminen SJ, Gueimonde M, Isolauri E (May 2005). "Probiotics that modify disease risk". The Journal of Nutrition 135 (5): 1294–8.  
  27. ^ Reid G, Jass J, Sebulsky MT, McCormick JK (October 2003). "Potential Uses of Probiotics in Clinical Practice". Clinical Microbiology Reviews 16 (4): 658–72.  
  28. ^ Kawai T, Akira S (February 2006). "Innate immune recognition of viral infection". Nature Immunology 7 (2): 131–7.  
  29. ^ Miller SB (August 2006). "Prostaglandins in health and disease: an overview". Seminars in Arthritis and Rheumatism 36 (1): 37–49.  
  30. ^ Ogawa Y, Calhoun WJ (October 2006). "The role of leukotrienes in airway inflammation". The Journal of Allergy and Clinical Immunology 118 (4): 789–98; quiz 799–800.  
  31. ^ Le Y, Zhou Y, Iribarren P, Wang J (April 2004). "Chemokines and chemokine receptors: their manifold roles in homeostasis and disease". Cellular & Molecular Immunology 1 (2): 95–104.  
  32. ^ Martin P, Leibovich SJ (November 2005). "Inflammatory cells during wound repair: the good, the bad and the ugly". Trends in Cell Biology 15 (11): 599–607.  
  33. ^ a b Rus H, Cudrici C, Niculescu F (2005). "The role of the complement system in innate immunity". Immunologic Research 33 (2): 103–12.  
  34. ^ Mayer, Gene (2006). "Immunology — Chapter Two: Complement". Microbiology and Immunology On-Line Textbook. USC School of Medicine. Retrieved 1 January 2007. 
  35. ^ a b c d e f g  
  36. ^ Liszewski MK, Farries TC, Lublin DM, Rooney IA, Atkinson JP (1996). "Control of the complement system". Advances in Immunology. Advances in Immunology 61: 201–83.  
  37. ^ Sim RB, Tsiftsoglou SA (February 2004). "Proteases of the complement system". Biochemical Society Transactions 32 (Pt 1): 21–7.  
  38. ^ Ryter A (1985). "Relationship between ultrastructure and specific functions of macrophages". Comparative Immunology, Microbiology and Infectious Diseases 8 (2): 119–33.  
  39. ^ Langermans JA, Hazenbos WL, van Furth R (September 1994). "Antimicrobial functions of mononuclear phagocytes". Journal of Immunological Methods 174 (1–2): 185–94.  
  40. ^ May RC, Machesky LM (March 2001). "Phagocytosis and the actin cytoskeleton". Journal of Cell Science 114 (Pt 6): 1061–77.  
  41. ^ Salzet M, Tasiemski A, Cooper E (2006). "Innate immunity in lophotrochozoans: the annelids". Current Pharmaceutical Design 12 (24): 3043–50.  
  42. ^ Zen K, Parkos CA (October 2003). "Leukocyte-epithelial interactions". Current Opinion in Cell Biology 15 (5): 557–64.  
  43. ^ a b Stvrtinová, Viera; Jakubovský, Ján; Hulín, Ivan (1995). from Pathophysiology: Principles of DiseaseInflammation and Fever . Computing Centre, Slovak Academy of Sciences: Academic Electronic Press. Retrieved 1 January 2007. 
  44. ^ Bowers, William (2006). "Immunology -Chapter Thirteen: Immunoregulation". Microbiology and Immunology On-Line Textbook. USC School of Medicine. Retrieved 4 January 2007. 
  45. ^ a b Guermonprez P, Valladeau J, Zitvogel L, Théry C, Amigorena S (2002). "Antigen presentation and T cell stimulation by dendritic cells". Annual Review of Immunology 20 (1): 621–67. PMID 11861614. doi:10.1146/annurev.immunol.20.100301.064828. 
  46. ^ Krishnaswamy G, Ajitawi O, Chi DS (2006). "The human mast cell: an overview". Methods in Molecular Biology 315: 13–34.  
  47. ^ Kariyawasam HH, Robinson DS (April 2006). "The eosinophil: the cell and its weapons, the cytokines, its locations". Seminars in Respiratory and Critical Care Medicine 27 (2): 117–27.  
  48. ^ Middleton D, Curran M, Maxwell L (August 2002). "Natural killer cells and their receptors". Transplant Immunology 10 (2–3): 147–64.  
  49. ^ Rajalingam R (2012). "Overview of the killer cell immunoglobulin-like receptor system". Methods in Molecular Biology (Clifton, N.J.). Methods in Molecular Biology™ 882: 391–414.  
  50. ^ Pancer Z, Cooper MD (2006). "The evolution of adaptive immunity". Annual Review of Immunology 24 (1): 497–518.  
  51. ^ a b Holtmeier W, Kabelitz D (2005). "gammadelta T cells link innate and adaptive immune responses". Chemical Immunology and Allergy. Chemical Immunology and Allergy 86: 151–83.  
  52. ^ Harty JT, Tvinnereim AR, White DW (2000). "CD8+ T cell effector mechanisms in resistance to infection". Annual Review of Immunology 18 (1): 275–308.  
  53. ^ a b Radoja S, Frey AB, Vukmanovic S (2006). "T-cell receptor signaling events triggering granule exocytosis". Critical Reviews in Immunology 26 (3): 265–90.  
  54. ^
  55. ^ McHeyzer-Williams LJ, Malherbe LP, McHeyzer-Williams MG (2006). "Helper T cell-regulated B cell immunity". Current Topics in Microbiology and Immunology. Current Topics in Microbiology and Immunology 311: 59–83.  
  56. ^ Kovacs B, Maus MV, Riley JL, et al. (November 2002). "Human CD8+ T cells do not require the polarization of lipid rafts for activation and proliferation". Proceedings of the National Academy of Sciences of the United States of America 99 (23): 15006–11.  
  57. ^ Grewal IS, Flavell RA (1998). "CD40 and CD154 in cell-mediated immunity". Annual Review of Immunology 16 (1): 111–35.  
  58. ^ Girardi M (January 2006). "Immunosurveillance and immunoregulation by gammadelta T cells". The Journal of Investigative Dermatology 126 (1): 25–31.  
  59. ^ "Understanding the Immune System: How it Works" ( 
  60. ^ a b Sproul TW, Cheng PC, Dykstra ML, Pierce SK (2000). "A role for MHC class II antigen processing in B cell development". International Reviews of Immunology 19 (2–3): 139–55.  
  61. ^ Kehry MR, Hodgkin PD (1994). "B-cell activation by helper T-cell membranes". Critical Reviews in Immunology 14 (3–4): 221–38.  
  62. ^ Bowers, William (2006). "Immunology — Chapter nine: Cells involved in immune responses". Microbiology and Immunology On-Line Textbook. USC School of Medicine. Retrieved 4 January 2007. 
  63. ^ Alder MN, Rogozin IB, Iyer LM, Glazko GV, Cooper MD, Pancer Z (December 2005). "Diversity and function of adaptive immune receptors in a jawless vertebrate". Science 310 (5756): 1970–3.  
  64. ^ Saji F, Samejima Y, Kamiura S, Koyama M (May 1999). "Dynamics of immunoglobulins at the feto-maternal interface". Reviews of Reproduction 4 (2): 81–9.  
  65. ^ Van de Perre P (July 2003). "Transfer of antibody via mother's milk". Vaccine 21 (24): 3374–6.  
  66. ^ Keller MA, Stiehm ER (October 2000). "Passive Immunity in Prevention and Treatment of Infectious Diseases". Clinical Microbiology Reviews 13 (4): 602–14.  
  67. ^ Death and DALY estimates for 2002 by cause for WHO Member States. World Health Organization. Retrieved on 1 January 2007.
  68. ^ Singh M, O'Hagan D (November 1999). "Advances in vaccine adjuvants". Nature Biotechnology 17 (11): 1075–81.  
  69. ^ Aw D, Silva AB, Palmer DB (April 2007). "Immunosenescence: emerging challenges for an ageing population". Immunology 120 (4): 435–46.  
  70. ^ a b c Chandra RK (August 1997). "Nutrition and the immune system: an introduction". The American Journal of Clinical Nutrition 66 (2): 460S–463S.  
  71. ^ Miller JF (July 2002). "The discovery of thymus function and of thymus-derived lymphocytes". Immunological Reviews 185 (1): 7–14.  
  72. ^ Joos L, Tamm M (2005). "Breakdown of pulmonary host defense in the immunocompromised host: cancer chemotherapy". Proceedings of the American Thoracic Society 2 (5): 445–8.  
  73. ^ Copeland KF, Heeney JL (December 1996). "T helper cell activation and human retroviral pathogenesis". Microbiological Reviews 60 (4): 722–42.  
  74. ^
  75. ^ a b c d
  76. ^ Bickle TA, Krüger DH (June 1993). "Biology of DNA restriction". Microbiological Reviews 57 (2): 434–50.  
  77. ^ Barrangou R, Fremaux C, Deveau H, et al. (March 2007). "CRISPR provides acquired resistance against viruses in prokaryotes". Science 315 (5819): 1709–12.  
  78. ^ Brouns SJ, Jore MM, Lundgren M, et al. (August 2008). "Small CRISPR RNAs guide antiviral defense in prokaryotes". Science 321 (5891): 960–4.  
  79. ^ Bayne C.J. (2003). Origins and evolutionary relationships between the innate and adaptive arms of immune systems. Integr. Comp. Biol. 43, 293–299.
  80. ^ Stram Y, Kuzntzova L (June 2006). "Inhibition of viruses by RNA interference". Virus Genes 32 (3): 299–306.  
  81. ^ a b Schneider, David (Spring 2005). "Innate Immunity — Lecture 4: Plant immune responses". Stanford University Department of Microbiology and Immunology. Retrieved 1 January 2007. 
  82. ^ Jones DG, Dangl JL (2006). "The plant immune system". Nature 444 (7117): 323–9.  
  83. ^ Baulcombe D (September 2004). "RNA silencing in plants". Nature 431 (7006): 356–63.  
  84. ^ Morgan RA, Dudley ME, Wunderlich JR, et al. (October 2006). "Cancer Regression in Patients After Transfer of Genetically Engineered Lymphocytes". Science 314 (5796): 126–9.  
  85. ^ a b Andersen MH, Schrama D, Thor Straten P, Becker JC (January 2006). "Cytotoxic T cells". The Journal of Investigative Dermatology 126 (1): 32–41.  
  86. ^ Boon T, van der Bruggen P (March 1996). "Human tumor antigens recognized by T lymphocytes". The Journal of Experimental Medicine 183 (3): 725–9.  
  87. ^ Castelli C, Rivoltini L, Andreola G, Carrabba M, Renkvist N, Parmiani G (March 2000). "T-cell recognition of melanoma-associated antigens". Journal of Cellular Physiology 182 (3): 323–31.  
  88. ^ a b Romero P, Cerottini JC, Speiser DE (2006). "The human T cell response to melanoma antigens". Advances in Immunology. Advances in Immunology 92: 187–224.  
  89. ^ a b Guevara-Patiño JA, Turk MJ, Wolchok JD, Houghton AN (2003). "Immunity to cancer through immune recognition of altered self: studies with melanoma". Advances in Cancer Research. Advances in Cancer Research 90: 157–77.  
  90. ^ Renkvist N, Castelli C, Robbins PF, Parmiani G (March 2001). "A listing of human tumor antigens recognized by T cells". Cancer Immunology, Immunotherapy 50 (1): 3–15.  
  91. ^ Gerloni M, Zanetti M (June 2005). "CD4 T cells in tumor immunity". Springer Seminars in Immunopathology 27 (1): 37–48.  
  92. ^ a b Seliger B, Ritz U, Ferrone S (January 2006). "Molecular mechanisms of HLA class I antigen abnormalities following viral infection and transformation". International Journal of Cancer 118 (1): 129–38.  
  93. ^ Hayakawa Y, Smyth MJ (2006). "Innate immune recognition and suppression of tumors". Advances in Cancer Research. Advances in Cancer Research 95: 293–322.  
  94. ^ a b Seliger B (2005). "Strategies of tumor immune evasion". BioDrugs 19 (6): 347–54.  
  95. ^ Frumento G, Piazza T, Di Carlo E, Ferrini S (September 2006). "Targeting tumor-related immunosuppression for cancer immunotherapy". Endocrine, Metabolic & Immune Disorders Drug Targets 6 (3): 233–7.  
  96. ^ Stix, Gary (July 2007). "A Malignant Flame" ( 
  97. ^ Wira, CR; Crane-Godreau M; Grant K (2004). "Endocrine regulation of the mucosal immune system in the female reproductive tract". In In: Ogra PL, Mestecky J, Lamm ME, Strober W, McGhee JR, Bienenstock J (eds.). Mucosal Immunology. San Francisco: Elsevier.  
  98. ^ Lang TJ (December 2004). "Estrogen as an immunomodulator". Clinical Immunology 113 (3): 224–30.  
    Moriyama A, Shimoya K, Ogata I, et al. (July 1999). "Secretory leukocyte protease inhibitor (SLPI) concentrations in cervical mucus of women with normal menstrual cycle". Molecular Human Reproduction 5 (7): 656–61.  
    Cutolo M, Sulli A, Capellino S, et al. (2004). "Sex hormones influence on the immune system: basic and clinical aspects in autoimmunity". Lupus 13 (9): 635–8.  
    King AE, Critchley HO, Kelly RW (February 2000). "Presence of secretory leukocyte protease inhibitor in human endometrium and first trimester decidua suggests an antibacterial protective role". Molecular Human Reproduction 6 (2): 191–6.  
  99. ^ Fimmel S, Zouboulis CC (2005). "Influence of physiological androgen levels on wound healing and immune status in men". The Aging Male 8 (3–4): 166–74.  
  100. ^ Dorshkind K, Horseman ND (June 2000). "The roles of prolactin, growth hormone, insulin-like growth factor-I, and thyroid hormones in lymphocyte development and function: insights from genetic models of hormone and hormone receptor deficiency". Endocrine Reviews 21 (3): 292–312.  
  101. ^ Nagpal S, Na S, Rathnachalam R (August 2005). "Noncalcemic actions of vitamin D receptor ligands". Endocrine Reviews 26 (5): 662–87.  
  102. ^ Marina Rode von Essen, Martin Kongsbak, Peter Schjerling, Klaus Olgaard, Niels Ødum & Carsten Geisler (2010). "Vitamin D controls T cell antigen receptor signaling and activation of human T cells". Nature Immunology 11 (4): 344–349.  
  103. ^ Sigmundsdottir H, Pan J, Debes GF, et al. (March 2007). "DCs metabolize sunlight-induced vitamin D3 to 'program' T cell attraction to the epidermal chemokine CCL27". Nat. Immunol. 8 (3): 285–93.  
  104. ^ Hertoghe T (December 2005). "The 'multiple hormone deficiency' theory of aging: is human senescence caused mainly by multiple hormone deficiencies?". Annals of the New York Academy of Sciences 1057 (1): 448–65.  
  105. ^ Klein JR (March 2006). "The Immune System as a Regulator of Thyroid Hormone Activity". Experimental Biology and Medicine 231 (3): 229–36.  
  106. ^ Leif Mosekilde (2005). "Vitamin D and the elderly". Clinical Endocrinology 62 (3): 265–281.  
  107. ^ Lange T, Perras B, Fehm HL, Born J (2003). "Sleep enhances the human antibody response to hepatitis A vaccination". Psychosomatic Medicine 65 (5): 831–5.  
  108. ^ Bryant PA, Trinder J, Curtis N (June 2004). "Sick and tired: Does sleep have a vital role in the immune system?". Nature Reviews Immunology 4 (6): 457–67.  
  109. ^ Krueger JM, Majde JA (May 2003). "Humoral links between sleep and the immune system: research issues". Annals of the New York Academy of Sciences 992 (1): 9–20.  
  110. ^ Majde JA, Krueger JM (December 2005). "Links between the innate immune system and sleep". The Journal of Allergy and Clinical Immunology 116 (6): 1188–98.  
  111. ^ "Sleep’s Effects On Your Immune System Revealed In New Body Clock Study". Retrieved 2014-04-28. 
  112. ^ Besedovsky L, Lange T, & Born J (2012). "Sleep and Immune Function". Pflugers Arch-Eur J Physiol 463: 121–137.  
  113. ^ Besedovsky L., Lange T., & Born J. (2012). "Sleep and Immune Function". Eur J Physiol 463: 121–137.  
  114. ^ "Can Better Sleep Mean Catching fewer Colds?". Retrieved 2014-04-28. 
  115. ^ , M. Serrano-Ríos, ed., CRC Press, 1994.Dairy products in human health and nutritionR.M. Suskind, C.L. Lachney, J.N. Udall, Jr., "Malnutrition and the Immune Response", in:
  116. ^ Pond CM (July 2005). "Adipose tissue and the immune system". Prostaglandins, Leukotrienes, and Essential Fatty Acids 73 (1): 17–30.  
  117. ^
  118. ^ a b Taylor AL, Watson CJ, Bradley JA (October 2005). "Immunosuppressive agents in solid organ transplantation: Mechanisms of action and therapeutic efficacy". Critical Reviews in Oncology/hematology 56 (1): 23–46.  
  119. ^ Barnes PJ (March 2006). "Corticosteroids: the drugs to beat". European Journal of Pharmacology 533 (1–3): 2–14.  
  120. ^ Masri MA (July 2003). "The mosaic of immunosuppressive drugs". Molecular Immunology 39 (17–18): 1073–7.  
  121. ^ Welling GW, Weijer WJ, van der Zee R, Welling-Wester S (September 1985). "Prediction of sequential antigenic regions in proteins". FEBS Letters 188 (2): 215–8.  
  122. ^ Söllner J, Mayer B (2006). "Machine learning approaches for prediction of linear B-cell epitopes on proteins".  
  123. ^ Saha S, Bhasin M, Raghava GP (2005). "Bcipep: A database of B-cell epitopes". BMC Genomics 6: 79.  
  124. ^ Flower DR, Doytchinova IA (2002). "Immunoinformatics and the prediction of immunogenicity". Applied Bioinformatics 1 (4): 167–76.  
  125. ^ a b Finlay BB, McFadden G (February 2006). "Anti-immunology: evasion of the host immune system by bacterial and viral pathogens". Cell 124 (4): 767–82.  
  126. ^ Cianciotto NP (December 2005). "Type II secretion: a protein secretion system for all seasons". Trends in Microbiology 13 (12): 581–8.  
  127. ^ Winstanley C, Hart CA (February 2001). "Type III secretion systems and pathogenicity islands". J. Med. Microbiol. 50 (2): 116–26.  
  128. ^ Finlay BB, Falkow S (June 1997). "Common themes in microbial pathogenicity revisited". Microbiol. Mol. Biol. Rev. 61 (2): 136–69.  
  129. ^ Kobayashi H (2005). "Airway biofilms: implications for pathogenesis and therapy of respiratory tract infections". Treatments in Respiratory Medicine 4 (4): 241–53.  
  130. ^ Housden NG, Harrison S, Roberts SE, et al. (June 2003). "Immunoglobulin-binding domains: Protein L from Peptostreptococcus magnus". Biochemical Society Transactions 31 (Pt 3): 716–8.  
  131. ^ Burton DR, Stanfield RL, Wilson IA (October 2005). "Antibody vs. HIV in a clash of evolutionary titans". Proceedings of the National Academy of Sciences of the United States of America 102 (42): 14943–8.  
  132. ^ Taylor JE, Rudenko G (November 2006). "Switching trypanosome coats: what's in the wardrobe?". Trends in Genetics 22 (11): 614–20.  
  133. ^ Cantin R, Méthot S, Tremblay MJ (June 2005). "Plunder and Stowaways: Incorporation of Cellular Proteins by Enveloped Viruses". Journal of Virology 79 (11): 6577–87.  

References

See also

The mechanisms used to evade the adaptive immune system are more complicated. The simplest approach is to rapidly change non-essential epitopes (amino acids and/or sugars) on the surface of the pathogen, while keeping essential epitopes concealed. This is called antigenic variation. An example is HIV, which mutates rapidly, so the proteins on its viral envelope that are essential for entry into its host target cell are constantly changing. These frequent changes in antigens may explain the failures of vaccines directed at this virus.[131] The parasite Trypanosoma brucei uses a similar strategy, constantly switching one type of surface protein for another, allowing it to stay one step ahead of the antibody response.[132] Masking antigens with host molecules is another common strategy for avoiding detection by the immune system. In HIV, the envelope that covers the virion is formed from the outermost membrane of the host cell; such "self-cloaked" viruses make it difficult for the immune system to identify them as "non-self" structures.[133]

An evasion strategy used by several pathogens to avoid the innate immune system is to hide within the cells of their host (also called intracellular pathogenesis). Here, a pathogen spends most of its life-cycle inside host cells, where it is shielded from direct contact with immune cells, antibodies and complement. Some examples of intracellular pathogens include viruses, the food poisoning bacterium Salmonella and the eukaryotic parasites that cause malaria (Plasmodium falciparum) and leishmaniasis (Leishmania spp.). Other bacteria, such as Mycobacterium tuberculosis, live inside a protective capsule that prevents lysis by complement.[128] Many pathogens secrete compounds that diminish or misdirect the host's immune response.[125] Some bacteria form biofilms to protect themselves from the cells and proteins of the immune system. Such biofilms are present in many successful infections, e.g., the chronic Pseudomonas aeruginosa and Burkholderia cenocepacia infections characteristic of cystic fibrosis.[129] Other bacteria generate surface proteins that bind to antibodies, rendering them ineffective; examples include Streptococcus (protein G), Staphylococcus aureus (protein A), and Peptostreptococcus magnus (protein L).[130]

The success of any pathogen depends on its ability to elude host immune responses. Therefore, pathogens evolved several methods that allow them to successfully infect a host, while evading detection or destruction by the immune system.[125] Bacteria often overcome physical barriers by secreting enzymes that digest the barrier, for example, by using a type II secretion system.[126] Alternatively, using a type III secretion system, they may insert a hollow tube into the host cell, providing a direct route for proteins to move from the pathogen to the host. These proteins are often used to shut down host defenses.[127]

Manipulation by pathogens

Larger drugs (>500 Da) can provoke a neutralizing immune response, particularly if the drugs are administered repeatedly, or in larger doses. This limits the effectiveness of drugs based on larger peptides and proteins (which are typically larger than 6000 Da). In some cases, the drug itself is not immunogenic, but may be co-administered with an immunogenic compound, as is sometimes the case for Taxol. Computational methods have been developed to predict the immunogenicity of peptides and proteins, which are particularly useful in designing therapeutic antibodies, assessing likely virulence of mutations in viral coat particles, and validation of proposed peptide-based drug treatments. Early techniques relied mainly on the observation that hydrophilic amino acids are overrepresented in epitope regions than hydrophobic amino acids;[121] however, more recent developments rely on machine learning techniques using databases of existing known epitopes, usually on well-studied virus proteins, as a training set.[122] A publicly accessible database has been established for the cataloguing of epitopes from pathogens known to be recognizable by B cells.[123] The emerging field of bioinformatics-based studies of immunogenicity is referred to as immunoinformatics.[124] Immunoproteomics is the study of large sets of proteins (proteomics) involved in the immune response.

Predicting immunogenicity

Cancer immunotherapy covers the medical ways to stimulate the immune system to attack cancer tumours.

Immunostimulation

[120] pathways.signal transduction prevent T cells from responding to signals correctly by inhibiting cyclosporin Immunosuppressive drugs such as [118]

[118][35]

Immunosuppression

The immune response can be manipulated to suppress unwanted responses resulting from autoimmunity, allergy, and transplant rejection, and to stimulate protective responses against pathogens that largely elude the immune system (see immunization) or cancer.

Manipulation in medicine

Foods rich in certain fatty acids may foster a healthy immune system.[116] Likewise, fetal undernourishment can cause a lifelong impairment of the immune system.[117]

Overnutrition is associated with diseases such as diabetes and obesity, which are known to affect immune function. More moderate malnutrition, as well as certain specific trace mineral and nutrient deficiencies, can also compromise the immune response.[115]

Nutrition and diet

In contrast, during wake periods differentiated effector cells, such as cytotoxic natural killer cells and CTLs, peak in order to elicit an effective response against any intruding pathogens. As well during awake active times, anti-inflammatory molecules, such as cortisol and catecholamines, peak. There are two theories as to why the pro-inflammatory state is reserved for sleep time. First, inflammation would cause serious cognitive and physical impairments if it were to occur during wake times. Second, inflammation may occur during sleep times due to the presence of melatonin. Inflammation causes a great deal of oxidative stress and the presence of melatonin during sleep times could actively counteract free radical production during this time.[113][114]

In addition to the negative consequences of sleep deprivation, sleep and the intertwined circadian system have been shown to have strong regulatory effects on immunological functions affecting both the innate and the adaptive immunity. First, during the early slow-wave-sleep stage, a sudden drop in blood levels of cortisol, epinephrine, and norepinephrine induce increased blood levels of the hormones leptin, pituitary growth hormone, and prolactin. These signals induce a pro-inflammatory state through the production of the pro-inflammatory cytokines interleukin-1, interleukin-12, TNF-alpha and IFN-gamma. These cytokines then stimulate immune functions such as immune cells activation, proliferation, and differentiation. It is during this time that undifferentiated, or less differentiated, like naïve and central memory T cells, peak (i.e. during a time of a slowly evolving adaptive immune response). In addition to these effects, the milieu of hormones produced at this time (leptin, pituitary growth hormone, and prolactin) support the interactions between APCs and T-cells, a shift of the Th1/Th2 cytokine balance towards one that supports Th1, an increase in overall Th cell proliferation, and naïve T cell migration to lymph nodes. This milieu is also thought to support the formation of long-lasting immune memory through the initiation of Th1 immune responses.[112]

When suffering from sleep deprivation, active immunizations may have a diminished effect and may result in lower antibody production, and a lower immune response, than would be noted in a well-rested individual. Additionally, proteins such as NFIL3, which have been shown to be closely intertwined with both T-cell differentiation and our circadian rhythms, can be affected through the disturbance of natural light and dark cycles through instances of sleep deprivation, shift work, etc. As a result these disruptions can lead to an increase in chronic conditions such as heart disease, chronic pain, and asthma.[111]

The immune system is affected by sleep and rest,[107] and sleep deprivation is detrimental to immune function.[108] Complex feedback loops involving cytokines, such as interleukin-1 and tumor necrosis factor-α produced in response to infection, appear to also play a role in the regulation of non-rapid eye movement (REM) sleep.[109] Thus the immune response to infection may result in changes to the sleep cycle, including an increase in slow-wave sleep relative to REM sleep.[110]

Sleep and Rest

It is conjectured that a progressive decline in hormone levels with age is partially responsible for weakened immune responses in aging individuals.[104] Conversely, some hormones are regulated by the immune system, notably thyroid hormone activity.[105] The age-related decline in immune function is also related to decreasing vitamin D levels in the elderly. As people age, two things happen that negatively affect their vitamin D levels. First, they stay indoors more due to decreased activity levels. This means that they get less sun and therefore produce less cholecalciferol via UVB radiation. Second, as a person ages the skin becomes less adept at producing vitamin D.[106]

When a T-cell encounters a foreign pathogen, it extends a vitamin D receptor. This is essentially a signaling device that allows the T-cell to bind to the active form of vitamin D, the steroid hormone calcitriol. T-cells have a symbiotic relationship with vitamin D. Not only does the T-cell extend a vitamin D receptor, in essence asking to bind to the steroid hormone version of vitamin D, calcitriol, but the T-cell expresses the gene CYP27B1, which is the gene responsible for converting the pre-hormone version of vitamin D, calcidiol into the steroid hormone version, calcitriol. Only after binding to calcitriol can T-cells perform their intended function. Other immune system cells that are known to express CYP27B1 and thus activate vitamin D calcidiol, are dendritic cells, keratinocytes and macrophages.[102][103]

Hormones can act as immunomodulators, altering the sensitivity of the immune system. For example, female sex hormones are known immunostimulators of both adaptive[97] and innate immune responses.[98] Some autoimmune diseases such as lupus erythematosus strike women preferentially, and their onset often coincides with puberty. By contrast, male sex hormones such as testosterone seem to be immunosuppressive.[99] Other hormones appear to regulate the immune system as well, most notably prolactin, growth hormone and vitamin D.[100][101]

Physiological regulation

Paradoxically, macrophages can promote tumor growth [96] when tumor cells send out cytokines that attract macrophages, which then generate cytokines and growth factors that nurture tumor development. In addition, a combination of hypoxia in the tumor and a cytokine produced by macrophages induces tumor cells to decrease production of a protein that blocks metastasis and thereby assists spread of cancer cells.

Clearly, some tumors evade the immune system and go on to become cancers.[94] Tumor cells often have a reduced number of MHC class I molecules on their surface, thus avoiding detection by killer T cells.[92] Some tumor cells also release products that inhibit the immune response; for example by secreting the cytokine TGF-β, which suppresses the activity of macrophages and lymphocytes.[95] In addition, immunological tolerance may develop against tumor antigens, so the immune system no longer attacks the tumor cells.[94]

The main response of the immune system to tumors is to destroy the abnormal cells using killer T cells, sometimes with the assistance of helper T cells.[88][91] Tumor antigens are presented on MHC class I molecules in a similar way to viral antigens. This allows killer T cells to recognize the tumor cell as abnormal.[92] NK cells also kill tumorous cells in a similar way, especially if the tumor cells have fewer MHC class I molecules on their surface than normal; this is a common phenomenon with tumors.[93] Sometimes antibodies are generated against tumor cells allowing for their destruction by the complement system.[89]

Another important role of the immune system is to identify and eliminate enzyme called tyrosinase that, when expressed at high levels, transforms certain skin cells (e.g. melanocytes) into tumors called melanomas.[87][88] A third possible source of tumor antigens are proteins normally important for regulating cell growth and survival, that commonly mutate into cancer inducing molecules called oncogenes.[85][89][90]

Macrophages have identified a cancer cell (the large, spiky mass). Upon fusing with the cancer cell, the macrophages (smaller white cells) inject toxins that kill the tumor cell. Immunotherapy for the treatment of cancer is an active area of medical research.[84]

Tumor immunology

Unlike animals, plants lack phagocytic cells, but many plant immune responses involve systemic chemical signals that are sent through a plant.[81] Individual plant cells respond to molecules associated with pathogens known as Pathogen-associated molecular patterns or PAMPs.[82] When a part of a plant becomes infected, the plant produces a localized hypersensitive response, whereby cells at the site of infection undergo rapid apoptosis to prevent the spread of the disease to other parts of the plant. Systemic acquired resistance (SAR) is a type of defensive response used by plants that renders the entire plant resistant to a particular infectious agent.[81] RNA silencing mechanisms are particularly important in this systemic response as they can block virus replication.[83]

Antimicrobial peptides called defensins are an evolutionarily conserved component of the innate immune response found in all animals and plants, and represent the main form of invertebrate systemic immunity.[1] The complement system and phagocytic cells are also used by most forms of invertebrate life. Ribonucleases and the RNA interference pathway are conserved across all eukaryotes, and are thought to play a role in the immune response to viruses.[80]

It is likely that a multicomponent, adaptive immune system arose with the first vertebrates, as invertebrates do not generate lymphocytes or an antibody-based humoral response.[1] Many species, however, utilize mechanisms that appear to be precursors of these aspects of vertebrate immunity. Immune systems appear even in the structurally most simple forms of life, with bacteria using a unique defense mechanism, called the restriction modification system to protect themselves from viral pathogens, called bacteriophages.[76] Prokaryotes also possess acquired immunity, through a system that uses CRISPR sequences to retain fragments of the genomes of phage that they have come into contact with in the past, which allows them to block virus replication through a form of RNA interference.[77][78] Offensive elements of the immune systems are also present in unicellular eukaryotes, but studies of their roles in defense are few.[79]

Other mechanisms and evolution

Hypersensitivity is an immune response that damages the body's own tissues. They are divided into four classes (Type I – IV) based on the mechanisms involved and the time course of the hypersensitive reaction. Type I hypersensitivity is an immediate or anaphylactic reaction, often associated with allergy. Symptoms can range from mild discomfort to death. Type I hypersensitivity is mediated by IgE, which triggers degranulation of mast cells and basophils when cross-linked by antigen.[75] Type II hypersensitivity occurs when antibodies bind to antigens on the patient's own cells, marking them for destruction. This is also called antibody-dependent (or cytotoxic) hypersensitivity, and is mediated by IgG and IgM antibodies.[75] Immune complexes (aggregations of antigens, complement proteins, and IgG and IgM antibodies) deposited in various tissues trigger Type III hypersensitivity reactions.[75] Type IV hypersensitivity (also known as cell-mediated or delayed type hypersensitivity) usually takes between two and three days to develop. Type IV reactions are involved in many autoimmune and infectious diseases, but may also involve contact dermatitis (poison ivy). These reactions are mediated by T cells, monocytes, and macrophages.[75]

Hypersensitivity

Overactive immune responses comprise the other end of immune dysfunction, particularly the autoimmune disorders. Here, the immune system fails to properly distinguish between self and non-self, and attacks part of the body. Under normal circumstances, many T cells and antibodies react with "self" peptides.[74] One of the functions of specialized cells (located in the thymus and bone marrow) is to present young lymphocytes with self antigens produced throughout the body and to eliminate those cells that recognize self-antigens, preventing autoimmunity.[60]

Autoimmunity

Immunodeficiencies can also be inherited or 'acquired'.[14] Chronic granulomatous disease, where phagocytes have a reduced ability to destroy pathogens, is an example of an inherited, or congenital, immunodeficiency. AIDS and some types of cancer cause acquired immunodeficiency.[72][73]

Immunodeficiencies occur when one or more of the components of the immune system are inactive. The ability of the immune system to respond to pathogens is diminished in both the young and the elderly, with immune responses beginning to decline at around 50 years of age due to immunosenescence.[69][70] In developed countries, obesity, alcoholism, and drug use are common causes of poor immune function.[70] However, malnutrition is the most common cause of immunodeficiency in developing countries.[70] Diets lacking sufficient protein are associated with impaired cell-mediated immunity, complement activity, phagocyte function, IgA antibody concentrations, and cytokine production. Additionally, the loss of the thymus at an early age through genetic mutation or surgical removal results in severe immunodeficiency and a high susceptibility to infection.[71]

Immunodeficiencies

The immune system is a remarkably effective structure that incorporates specificity, inducibility and adaptation. Failures of host defense do occur, however, and fall into three broad categories: immunodeficiencies, autoimmunity, and hypersensitivities.

Disorders of human immunity

Most viral toxin components.[14] Since many antigens derived from acellular vaccines do not strongly induce the adaptive response, most bacterial vaccines are provided with additional adjuvants that activate the antigen-presenting cells of the innate immune system and maximize immunogenicity.[68]

[67][35] This deliberate induction of an immune response is successful because it exploits the natural specificity of the immune system, as well as its inducibility. With infectious disease remaining one of the leading causes of death in the human population, vaccination represents the most effective manipulation of the immune system mankind has developed.[14] memory is acquired following infection by activation of B and T cells. Active immunity can also be generated artificially, through active Long-term

Active memory and immunization

The time-course of an immune response begins with the initial pathogen encounter, (or initial vaccination) and leads to the formation and maintenance of active immunological memory.

Newborn infants have no prior exposure to microbes and are particularly vulnerable to infection. Several layers of passive protection are provided by the mother. During pregnancy, a particular type of antibody, called IgG, is transported from mother to baby directly across the placenta, so human babies have high levels of antibodies even at birth, with the same range of antigen specificities as their mother.[64] Breast milk or colostrum also contains antibodies that are transferred to the gut of the infant and protect against bacterial infections until the newborn can synthesize its own antibodies.[65] This is passive immunity because the fetus does not actually make any memory cells or antibodies—it only borrows them. This passive immunity is usually short-term, lasting from a few days up to several months. In medicine, protective passive immunity can also be transferred artificially from one individual to another via antibody-rich serum.[66]

Passive memory

When B cells and T cells are activated and begin to replicate, some of their offspring become long-lived memory cells. Throughout the lifetime of an animal, these memory cells remember each specific pathogen encountered and can mount a strong response if the pathogen is detected again. This is "adaptive" because it occurs during the lifetime of an individual as an adaptation to infection with that pathogen and prepares the immune system for future challenges. Immunological memory can be in the form of either passive short-term memory or active long-term memory.

Immunological memory

Evolution of the adaptive immune system occurred in an ancestor of the jawed vertebrates. Many of the classical molecules of the adaptive immune system (e.g., immunoglobulins and T cell receptors) exist only in jawed vertebrates. However, a distinct lymphocyte-derived molecule has been discovered in primitive jawless vertebrates, such as the lamprey and hagfish. These animals possess a large array of molecules called Variable lymphocyte receptors (VLRs) that, like the antigen receptors of jawed vertebrates, are produced from only a small number (one or two) of genes. These molecules are believed to bind pathogenic antigens in a similar way to antibodies, and with the same degree of specificity.[63]

Alternative adaptive immune system

A B cell identifies pathogens when antibodies on its surface bind to a specific foreign antigen.[60] This antigen/antibody complex is taken up by the B cell and processed by proteolysis into peptides. The B cell then displays these antigenic peptides on its surface MHC class II molecules. This combination of MHC and antigen attracts a matching helper T cell, which releases lymphokines and activates the B cell.[61] As the activated B cell then begins to divide, its offspring (plasma cells) secrete millions of copies of the antibody that recognizes this antigen. These antibodies circulate in blood plasma and lymph, bind to pathogens expressing the antigen and mark them for destruction by complement activation or for uptake and destruction by phagocytes. Antibodies can also neutralize challenges directly, by binding to bacterial toxins or by interfering with the receptors that viruses and bacteria use to infect cells.[62]

B lymphocytes and antibodies

An antibody is made up of two heavy chains and two light chains. The unique variable region allows an antibody to recognize its matching antigen.[59]

Gamma delta T cells (γδ T cells) possess an alternative T cell receptor (TCR) as opposed to CD4+ and CD8+ (αβ) T cells and share the characteristics of helper T cells, cytotoxic T cells and NK cells. The conditions that produce responses from γδ T cells are not fully understood. Like other 'unconventional' T cell subsets bearing invariant TCRs, such as CD1d-restricted Natural Killer T cells, γδ T cells straddle the border between innate and adaptive immunity.[58] On one hand, γδ T cells are a component of adaptive immunity as they rearrange TCR genes to produce receptor diversity and can also develop a memory phenotype. On the other hand, the various subsets are also part of the innate immune system, as restricted TCR or NK receptors may be used as pattern recognition receptors. For example, large numbers of human Vγ9/Vδ2 T cells respond within hours to common molecules produced by microbes, and highly restricted Vδ1+ T cells in epithelia respond to stressed epithelial cells.[51]

Gamma delta T cells

Helper T cells express T cell receptors (TCR) that recognize antigen bound to Class II MHC molecules. The MHC:antigen complex is also recognized by the helper cell's CD4 co-receptor, which recruits molecules inside the T cell (e.g., Lck) that are responsible for the T cell's activation. Helper T cells have a weaker association with the MHC:antigen complex than observed for killer T cells, meaning many receptors (around 200–300) on the helper T cell must be bound by an MHC:antigen in order to activate the helper cell, while killer T cells can be activated by engagement of a single MHC:antigen molecule. Helper T cell activation also requires longer duration of engagement with an antigen-presenting cell.[56] The activation of a resting helper T cell causes it to release cytokines that influence the activity of many cell types. Cytokine signals produced by helper T cells enhance the microbicidal function of macrophages and the activity of killer T cells.[14] In addition, helper T cell activation causes an upregulation of molecules expressed on the T cell's surface, such as CD40 ligand (also called CD154), which provide extra stimulatory signals typically required to activate antibody-producing B cells.[57]

Helper T cells regulate both the innate and adaptive immune responses and help determine which immune responses the body makes to a particular pathogen.[54][55] These cells have no cytotoxic activity and do not kill infected cells or clear pathogens directly. They instead control the immune response by directing other cells to perform these tasks.

Function of T helper cells: Antigen-presenting cells (APCs) present antigen on their Class II MHC molecules (MHC2). Helper T cells recognize these, with the help of their expression of CD4 co-receptor (CD4+). The activation of a resting helper T cell causes it to release cytokines and other stimulatory signals (green arrows) that stimulate the activity of macrophages, killer T cells and B cells, the latter producing antibodies. The stimulation of B cells and macrophages succeeds a proliferation of T helper cells.

Helper T cells

Killer T cells are a sub-group of T cells that kill cells that are infected with viruses (and other pathogens), or are otherwise damaged or dysfunctional.[52] As with B cells, each type of T cell recognizes a different antigen. Killer T cells are activated when their T cell receptor (TCR) binds to this specific antigen in a complex with the MHC Class I receptor of another cell. Recognition of this MHC:antigen complex is aided by a co-receptor on the T cell, called CD8. The T cell then travels throughout the body in search of cells where the MHC I receptors bear this antigen. When an activated T cell contacts such cells, it releases cytotoxins, such as perforin, which form pores in the target cell's plasma membrane, allowing ions, water and toxins to enter. The entry of another toxin called granulysin (a protease) induces the target cell to undergo apoptosis.[53] T cell killing of host cells is particularly important in preventing the replication of viruses. T cell activation is tightly controlled and generally requires a very strong MHC/antigen activation signal, or additional activation signals provided by "helper" T cells (see below).[53]

Killer T cells

In contrast, the B cell antigen-specific receptor is an antibody molecule on the B cell surface, and recognizes whole pathogens without any need for antigen processing. Each lineage of B cell expresses a different antibody, so the complete set of B cell antigen receptors represent all the antibodies that the body can manufacture.[35]

Both B cells and T cells carry receptor molecules that recognize specific targets. T cells recognize a "non-self" target, such as a pathogen, only after antigens (small fragments of the pathogen) have been processed and presented in combination with a "self" receptor called a major histocompatibility complex (MHC) molecule. There are two major subtypes of T cells: the killer T cell and the helper T cell. In addition there are suppressor T cells which have a role in modulating immune response. Killer T cells only recognize antigens coupled to Class I MHC molecules, while helper T cells only recognize antigens coupled to Class II MHC molecules. These two mechanisms of antigen presentation reflect the different roles of the two types of T cell. A third, minor subtype are the γδ T cells that recognize intact antigens that are not bound to MHC receptors.[51]

The cells of the adaptive immune system are special types of leukocytes, called lymphocytes. B cells and T cells are the major types of lymphocytes and are derived from hematopoietic stem cells in the bone marrow.[35] B cells are involved in the humoral immune response, whereas T cells are involved in cell-mediated immune response.

Lymphocytes

The adaptive immune system evolved in early vertebrates and allows for a stronger immune response as well as immunological memory, where each pathogen is "remembered" by a signature antigen.[50] The adaptive immune response is antigen-specific and requires the recognition of specific "non-self" antigens during a process called antigen presentation. Antigen specificity allows for the generation of responses that are tailored to specific pathogens or pathogen-infected cells. The ability to mount these tailored responses is maintained in the body by "memory cells". Should a pathogen infect the body more than once, these specific memory cells are used to quickly eliminate it.

Adaptive immune system

Natural killer cells, or NK cells, are a component of the innate immune system which does not directly attack invading microbes. Rather, NK cells destroy compromised host cells, such as tumor cells or virus-infected cells, recognizing such cells by a condition known as "missing self." This term describes cells with low levels of a cell-surface marker called MHC I (major histocompatibility complex) – a situation that can arise in viral infections of host cells.[35] They were named "natural killer" because of the initial notion that they do not require activation in order to kill cells that are "missing self." For many years it was unclear how NK cells recognize tumor cells and infected cells. It is now known that the MHC makeup on the surface of those cells is altered and the NK cells become activated through recognition of "missing self". Normal body cells are not recognized and attacked by NK cells because they express intact self MHC antigens. Those MHC antigens are recognized by killer cell immunoglobulin receptors (KIR) which essentially put the brakes on NK cells.[49]

Natural killer cells

Mast cells reside in connective tissues and mucous membranes, and regulate the inflammatory response.[46] They are most often associated with allergy and anaphylaxis.[43] Basophils and eosinophils are related to neutrophils. They secrete chemical mediators that are involved in defending against parasites and play a role in allergic reactions, such as asthma.[47] Natural killer (NK cells) cells are leukocytes that attack and destroy tumor cells, or cells that have been infected by viruses.[48]

Dendritic cells (DC) are phagocytes in tissues that are in contact with the external environment; therefore, they are located mainly in the skin, nose, lungs, stomach, and intestines.[45] They are named for their resemblance to neuronal dendrites, as both have many spine-like projections, but dendritic cells are in no way connected to the nervous system. Dendritic cells serve as a link between the bodily tissues and the innate and adaptive immune systems, as they present antigen to T cells, one of the key cell types of the adaptive immune system.[45]

Neutrophils and macrophages are phagocytes that travel throughout the body in pursuit of invading pathogens.[42] Neutrophils are normally found in the bloodstream and are the most abundant type of phagocyte, normally representing 50% to 60% of the total circulating leukocytes.[43] During the acute phase of inflammation, particularly as a result of bacterial infection, neutrophils migrate toward the site of inflammation in a process called chemotaxis, and are usually the first cells to arrive at the scene of infection. Macrophages are versatile cells that reside within tissues and produce a wide array of chemicals including enzymes, complement proteins, and regulatory factors such as interleukin 1.[44] Macrophages also act as scavengers, ridding the body of worn-out cells and other debris, and as antigen-presenting cells that activate the adaptive immune system.[12]

Phagocytosis is an important feature of cellular innate immunity performed by cells called 'phagocytes' that engulf, or eat, pathogens or particles. Phagocytes generally patrol the body searching for pathogens, but can be called to specific locations by cytokines.[14] Once a pathogen has been engulfed by a phagocyte, it becomes trapped in an intracellular vesicle called a phagosome, which subsequently fuses with another vesicle called a lysosome to form a phagolysosome. The pathogen is killed by the activity of digestive enzymes or following a respiratory burst that releases free radicals into the phagolysosome.[38][39] Phagocytosis evolved as a means of acquiring nutrients, but this role was extended in phagocytes to include engulfment of pathogens as a defense mechanism.[40] Phagocytosis probably represents the oldest form of host defense, as phagocytes have been identified in both vertebrate and invertebrate animals.[41]

[12].adaptive immune system Innate cells are also important mediators in the activation of the [35]