면역관용: 두 판 사이의 차이

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새 문서: {{초안 문서}} '''면역관용'''(immune tolerance, immunological tolerance, immunotolerance)은 면역 반응을 이끌어낼 수 있는 능력이 있는 물질이나 조직에 대한 면역계의 무반응 상태이다. 이 상태는 특정 항원에 대해 사전에 노출되었을 때 유도되며<ref name="nobel lecture">{{웹 인용|url=https://www.nobelprize.org/nobel_prizes/medicine/laureates/1960/medawar-lecture.html|제목=Nobel Lecture: Immunological Tolera...
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2022년 4월 19일 (화) 05:35 판

일반 이름공간에 {{초안 문서}} 틀을 사용하지 마십시오. 면역관용(immune tolerance, immunological tolerance, immunotolerance)은 면역 반응을 이끌어낼 수 있는 능력이 있는 물질이나 조직에 대한 면역계의 무반응 상태이다. 이 상태는 특정 항원에 대해 사전에 노출되었을 때 유도되며[1][2], 흔히 일어나는 외래 항원이 들어오면 면역에 의해 제거되는 현상과 대조된다.(면역 반응 참조). 면역관용은 상태가 유도된 것이 가슴샘과 골수인지(중추), 또는 다른 조직과 림프절인지(말초)에 따라 중추관용과 말초관용으로 분류된다. 이러한 형태의 내성이 생기는 기전은 다르지만 결과적으로 나타나는 효과는 유사하다.

면역관용은 정상 생리를 유지하는 데에 중요하다. 중추관용은 면역계가 자기(self)와 비자기(non-self)를 구별하는 법을 배우는 중요한 방법이다. 말초관용은 다양한 환경 물질(알레르겐, 장내 미생물 등)에 대한 면역계의 과민반응을 예방하는 데 중요하다. 중추관용이나 말초관용이 결핍되면 자가 면역 질환을 유발하여 전신 홍반성 루푸스,[3] 류마티스 관절염, 제1형 당뇨병,[4] 자가면역 다내분비 증후군 1형(APS-1),[5] IPEX 증후군[6]과 같은 다양한 증후군의 원인이 된다. 또한 천식, 알레르기,[7] 염증성 장 질환 발생에 잠재적으로 기여할 수 있다.[4] 그리고 임신 중 면역관용은 어미 동물이 유산을 방지할 수 있을 만큼 충분히 억제된 동종면역 반응을 가지도록 해서, 유전적으로 구별되는 자손을 잉태할 수 있게 해준다.

그러나 면역관용에는 부정적인 면도 있다. 일부 병원성 미생물은 면역관용을 이용해 숙주를 성공적으로 감염시키고 면역계의 공격을 회피할 수 있다.[8] 또한, 다수의 종양은 국소 미세 환경에서 말초관용을 유도하여 숙주 면역계에 의해 제거되는 것을 방지한다.[9]

역사적 배경

면역관용 현상은 1945년 레이 데이비드 오웬(Ray D. Owen)에 의해 처음 기술되었다. 그는 같은 태반을 공유하는 이란성 쌍둥이 소가 서로의 적혈구가 안정적으로 혼합되어 존재(반드시 50:50 비율은 아님)하며, 그 혼합물을 평생 유지한다는 점에 주목했다.[1] 오웬은 면역관용이라는 용어를 사용하지 않았지만 그의 연구는 신체가 이러한 외부 조직에 관대하게 반응할 수 있다는 것을 보여주었다. 이 관찰은 1953년 Leslie Brent, Rupert E. Billingham, 피터 메더워(Peter Medawar)에 의해 실험적으로 검증되었으며, 이들은 태아나 신생아 생쥐에 외래 세포를 주입하여 나중에 동일한 외래 기증자의 이식을 수용할 수 있음을 보여주었다. 그러나 그들은 그 당시 그들의 연구의 면역학적 의의에 대해 생각하지는 못했다. 메더워는 이후 1960년 노벨생리의학상을 수상할 때 다음과 같이 밝혔다.

"우리는 오웬이 설명한 현상의 면역학적 결과를 연구할 생각을 염두에 두고 시작한 것이 아니라 반대로 HP Donald 박사의 지시에 따라 일란성 쌍둥이와 이성 쌍둥이를 구별할 수 있는 확실한 방법을 고안하려고 했습니다. . . ." [1]

그러나 이러한 발견은 면역관용을 유지하기 위해 자가 반응성 림프구가 제거된다는 개념을 최초로 제안한 프랭크 맥팔레인 버넷 경(Sir Frank MacFarlane Burnet)과 프랭크 페너(Frank Fenner)가 공식화한 면역관용 이론에 중대한 영향을 미쳤다. 림프구가 제거된다는 개념은 현재는 클론소거라고 부른다.[10] 버넷과 메더워는 궁극적으로 '후천성 면역관용의 발견'이라는 공로를 인정받았고 1960년 노벨 생리학·의학상을 공동 수상했다.[1]

정의와 이용

메더워와 버넷은 노벨상 수상 후 강의에서 면역관용을 '일반적으로 면역학적 반응을 유발할 것으로 예상되는 물질에 대한 무관심, 또는 무반응 상태'로 정의했다.[1] 다른 최신 정의는 이와 거의 동일하게 유지되었다. Janeway's Immunobiology 8판에서는 면역관용을 '다른 조직에 면역학적으로 무반응한 것'으로 정의했다.[2]

면역관용은 신체가 특정 약제에 대한 면역 반응을 감소시키거나 없애는 생리학적 기전도 포함한다. 자기(self)와 비자기(non-self)의 구별, 알레르기 반응 억제, 병원체를 거부하고 제거하는 대신 만성 감염을 허용하는 현상, 모체 면역계가 태아를 공격하는 일을 방지하는 현상 등 여러 현상들을 설명하는 데 이용된다. 일반적으로 면역관용은 항원이 아닌 숙주의 변화로 인해 발생한다.[1] 일부 병원체는 숙주-병원체 공진화(co-evolution)를 통해 독성이 감소하는 쪽으로 진화할 수 있지만.[11] 면역관용은 병원체의 변화를 나타내는 것이 아니라 숙주의 생리적인 변화를 설명하는 데 사용된다. 또한 일반적으로 코르티코스테로이드, 림프독성 화학요법 약제, 치사량 이하의 방사선 등에 의해 인위적으로 유도된 면역억제는 면역관용에 포함되지 않는다. 또한 면역학적 마비와 같은 다른 유형의 무반응도 포함되지 않는다.[12] 면역억제나 마비 같은 경우 숙주에 생리적인 문제가 생기지만 근본적으로 바뀌지는 않는다.

면역관용은 보통 중추면역관용과 말초면역관용으로 구분된다.[2] 그러나 '자연적'(natural), 또는 '후천적'(acquired) 내성과 같은 다른 용어들이 생리학적 수단, 인공적이거나 실험적인 수단, 약리학적 수단 등에 의한 관용을 나타내기 위해 때때로 사용되었다.[13] 이 두 가지 분류 방법은 때때로 혼동되지만 동등하지 않다. 중추와 말초면역관용은 모두 자연적으로 존재하며, 실험적으로 유도될 수도 있다. 이 차이를 염두에 두는 것이 중요하다.

중추면역관용

중추면역관용은 자가반응성 림프구 클론이 완전한 면역 세포로 발달하기 전에 삭제하는 방식으로 생기는 면역관용이다. 가슴샘[14][15]ㄱ 골수 T 및 B 림프구 의 골수 에서 발생합니다. 이 조직에서 성숙 림프구는 수질 흉선 상피 세포 와 흉선 수지상 세포 또는 골수 세포 가 제시하는 자가 항원에 노출됩니다. 자가항원은 내인성 발현, 순환혈액을 통한 말초부위의 항원 유입, 흉선 기질 세포의 경우 전사 인자 AIRE 의 작용에 의한 다른 비-흉선 조직의 단백질 발현으로 인해 존재한다.

Central tolerance refers to the tolerance established by deleting autoreactive lymphocyte clones before they develop into fully immunocompetent cells. It occurs during lymphocyte development in the thymus[16][17] and bone marrow for T and B lymphocytes, respectively. In these tissues, maturing lymphocytes are exposed to self-antigens presented by medullary thymic epithelial cells and thymic dendritic cells, or bone marrow cells. Self-antigens are present due to endogenous expression, importation of antigen from peripheral sites via circulating blood, and in the case of thymic stromal cells, expression of proteins of other non-thymic tissues by the action of the transcription factor AIRE.

Those lymphocytes that have receptors that bind strongly to self-antigens are removed by induction of apoptosis of the autoreactive cells, or by induction of anergy, a state of non-activity.[18] Weakly autoreactive B cells may also remain in a state of immunological ignorance where they simply do not respond to stimulation of their B cell receptor. Some weakly self-recognizing T cells are alternatively differentiated into natural regulatory T cells (nTreg cells), which act as sentinels in the periphery to calm down potential instances of T cell autoreactivity (see peripheral tolerance below).[2]

The deletion threshold is much more stringent for T cells than for B cells since T cells alone can cause direct tissue damage. Furthermore, it is more advantageous for the organism to let its B cells recognize a wider variety of antigen so it can produce antibodies against a greater diversity of pathogens. Since the B cells can only be fully activated after confirmation by more self-restricted T cells that recognize the same antigen, autoreactivity is held in check.[18]

This process of negative selection ensures that T and B cells that could initiate a potent immune response to the host's own tissues are eliminated while preserving the ability to recognize foreign antigens. It is the step in lymphocyte education that is key for preventing autoimmunity (entire process detailed here). Lymphocyte development and education is most active in fetal development but continues throughout life as immature lymphocytes are generated, slowing as the thymus degenerates and the bone marrow shrinks in adult life.

Peripheral tolerance

Peripheral tolerance develops after T and B cells mature and enter the peripheral tissues and lymph nodes.[2] It is established by a number of partly overlapping mechanisms that mostly involve control at the level of T cells, especially CD4+ helper T cells, which orchestrate immune responses and give B cells the confirmatory signals they need in order to produce antibodies. Inappropriate reactivity toward normal self-antigen that was not eliminated in the thymus can occur, since the T cells that leave the thymus are relatively but not completely safe. Some will have receptors (TCRs) that can respond to self-antigens that:

  • are present in such high concentration outside the thymus that they can bind to "weak" receptors.
  • the T cell did not encounter in the thymus (such as, tissue-specific molecules like those in the islets of Langerhans, brain, or spinal cord not expressed by AIRE in thymic tissues).

Those self-reactive T cells that escape intrathymic negative selection in the thymus can inflict cell injury unless they are deleted or effectively muzzled in the peripheral tissue chiefly by nTreg cells (see central tolerance above).

Appropriate reactivity toward certain antigens can also be quieted by induction of tolerance after repeated exposure, or exposure in a certain context. In these cases, there is a differentiation of naïve CD4+ helper T cells into induced Treg cells (iTreg cells) in the peripheral tissue or nearby lymphoid tissue (lymph nodes, mucosal-associated lymphoid tissue, etc.). This differentiation is mediated by IL-2 produced upon T cell activation, and TGF-β from any of a variety of sources, including tolerizing dendritic cells (DCs), other antigen presenting cells, or in certain conditions surrounding tissue.[8]

Treg cells are not the only cells that mediate peripheral tolerance. Other regulatory immune cells include T cell subsets similar to but phenotypically distinct from Treg cells, including TR1 cells that make IL-10 but do not express Foxp3, TGF-β-secreting TH3 cells, as well as other less well-characterized cells that help establish a local tolerogenic environment.[19] B cells also express CD22, a non-specific inhibitor receptor that dampens B cell receptor activation. A subset of B regulatory cells that makes IL-10 and TGF-β also exists.[20] Some DCs can make Indoleamine 2,3-dioxygenase (IDO) that depletes the amino acid tryptophan needed by T cells to proliferate and thus reduce responsiveness. DCs also have the capacity to directly induce anergy in T cells that recognize antigen expressed at high levels and thus presented at steady-state by DCs.[21] In addition, FasL expression by immune privileged tissues can result in activation-induced cell death of T cells.[22]

nTreg vs. iTreg cells

The involvement of T cells, later classified as Treg cells, in immune tolerance was recognized in 1995 when animal models showed that CD4+ CD25+ T cells were necessary and sufficient for the prevention of autoimmunity in mice and rats.[19] Initial observations showed removal of the thymus of a newborn mouse resulted in autoimmunity, which could be rescued by transplantation of CD4+ T cells. A more specific depletion and reconstitution experiment established the phenotype of these cells as CD4+ and CD25+. Later in 2003, experiments showed that Treg cells were characterized by the expression of the Foxp3 transcription factor, which is responsible for the suppressive phenotype of these cells.[19]

It was assumed that, since the presence of the Treg cells originally characterized was dependent on the neonatal thymus, these cells were thymically derived. By the mid-2000s, however, evidence was accruing of conversion of naïve CD4+ T cells to Treg cells outside of the thymus.[8] These were later defined as induced or iTreg cells to contrast them with thymus-derived nTreg cells. Both types of Treg cells quieten autoreactive T cell signaling and proliferation by cell-contact-dependent and -independent mechanisms including:[23]

  • Contact-dependent:
  • Contact-independent
  • Secretion of TGF-β, which sensitizes cells to suppression and promotes Treg-like cell differentiation
  • Secretion of IL-10
  • Cytokine absorption leading to cytokine deprivation-mediated apoptosis

nTreg cells and iTreg cells, however, have a few important distinguishing characteristics that suggest they have different physiological roles:[8]

  • nTreg cells develop in the thymus; iTreg cells develop outside the thymus in chronically inflamed tissue, lymph nodes, spleen, and gut-associated lymphoid tissue (GALT).
  • nTreg cells develop from Foxp3- CD25+ CD4+ cells while iTreg cells develop from Foxp3+ CD25- CD4- cells (both become Foxp3+ CD25+CD4+).
  • nTreg cells, when activated, require CD28 costimulation, while iTreg cells require CTLA-4 costimulation.
  • nTreg cells are specific, modestly, for self-antigen while iTreg cells recognize allergens, commensal bacteria, tumor antigens, alloantigens, and self-antigens in inflamed tissue.

Tolerance in physiology and medicine

Allograft tolerance

Immune recognition of non-self-antigens typically complicates transplantation and engrafting of foreign tissue from an organism of the same species (allografts), resulting in graft reaction. However, there are two general cases in which an allograft may be accepted. One is when cells or tissue are grafted to an immune-privileged site that is sequestered from immune surveillance (like in the eye or testes) or has strong molecular signals in place to prevent dangerous inflammation (like in the brain). The second is when a state of tolerance has been induced, either by previous exposure to the antigen of the donor in a manner that causes immune tolerance rather than sensitization in the recipient, or after chronic rejection. Long-term exposure to a foreign antigen from fetal development or birth may result in establishment of central tolerance, as was observed in Medawar's mouse-allograft experiments.[1] In usual transplant cases, however, such early prior exposure is not possible. Nonetheless, a few patients can still develop allograft tolerance upon cessation of all exogenous immunosuppressive therapy, a condition referred to as operational tolerance.[24][25] CD4+ Foxp3+ Treg cells, as well as CD8+ CD28- regulatory T cells that dampen cytotoxic responses to grafted organs, are thought to play a role.[18] In addition, genes involved in NK cell and γδT cell function associated with tolerance have been implicated for liver transplant patients.[25] The unique gene signatures of these patients implies their physiology may be predisposed toward immune tolerance.

Fetal development

<nowiki /> 이 부분의 본문은 Immune tolerance in pregnancy입니다.

The fetus has a different genetic makeup than the mother, as it also translates its father's genes, and is thus perceived as foreign by the maternal immune system. Women who have borne multiple children by the same father typically have antibodies against the father's red blood cell and major histocompatibility complex (MHC) proteins.[2] However, the fetus usually is not rejected by the mother, making it essentially a physiologically tolerated allograft. It is thought that the placental tissues which interface with maternal tissues not only try to escape immunological recognition by downregulating identifying MHC proteins but also actively induce a marked peripheral tolerance. Placental trophoblast cells express a unique Human Leukocyte Antigen (HLA-G) that inhibits attack by maternal NK cells. These cells also express IDO, which represses maternal T cell responses by amino acid starvation. Maternal T cells specific for paternal antigens are also suppressed by tolerogenic DCs and activated iTregs or cross-reacting nTregs.[26] Some maternal Treg cells also release soluble fibrinogen-like proteins 2 (sFGL2), which suppresses the function of DCs and macrophages involved in inflammation and antigen presentation to reactive T cells[26] These mechanisms altogether establish an immune-privileged state in the placenta that protects the fetus. A break in this peripheral tolerance results in miscarriage and fetal loss.[27] (for more information, see Immune tolerance in pregnancy).

The microbiome

The skin and digestive tract of humans and many other organisms is colonized with an ecosystem of microorganisms that is referred to as the microbiome. Though in mammals a number of defenses exist to keep the microbiota at a safe distance, including a constant sampling and presentation of microbial antigens by local DCs, most organisms do not react against commensal microorganisms and tolerate their presence. Reactions are mounted, however, to pathogenic microbes and microbes that breach physiological barriers. Peripheral mucosal immune tolerance, in particular, mediated by iTreg cells and tolerogenic antigen-presenting cells, is thought to be responsible for this phenomenon. In particular, specialized gut CD103+ DCs that produce both TGF-β and retinoic acid efficiently promotes the differentiation of iTreg cells in the gut lymphoid tissue.[8] Foxp3- TR1 cells that make IL-10 are also enriched in the intestinal lining.[2] Break in this tolerance is thought to underlie the pathogenesis of inflammatory bowel diseases like Crohn's disease and ulcerative colitis.[4]

Oral tolerance and hypersensitivity

<nowiki /> Goblet cell § Role in oral tolerance 문서를 참고하십시오.

Oral tolerance refers to a specific type of peripheral tolerance induced by antigens given by mouth and exposed to the gut mucosa and its associated lymphoid tissues.[13] The hypo-responsiveness induced by oral exposure is systemic and can reduce hypersensitivity reactions in certain cases. Records from 1829 indicate that American Indians would reduce contact hypersensitivity from poison ivy by consuming leaves of related Rhus species; however, contemporary attempts to use oral tolerance to ameliorate autoimmune diseases like rheumatoid arthritis and other hypersensitivity reactions have been mixed.[13] The systemic effects of oral tolerance may be explained by the extensive recirculation of immune cells primed in one mucosal tissue in another mucosal tissue, allowing extension of mucosal immunity.[28] The same probably occurs for cells mediating mucosal immune tolerance.

Oral tolerance may depend on the same mechanisms of peripheral tolerance that limit inflammation to bacterial antigens in the microbiome since both involve the gut-associated lymphoid tissue. It may also have evolved to prevent hypersensitivity reactions to food proteins.[29] It is of immense immunological importance, since it is a continuous natural immunologic event driven by exogenous antigen.

Allergy and hypersensitivity reactions in general are traditionally thought of as misguided or excessive reactions by the immune system, possibly due to broken or underdeveloped mechanisms of peripheral tolerance. Usually, Treg cells, TR1, and Th3 cells at mucosal surfaces suppress type 2 CD4 helper cells, mast cells, and eosinophils, which mediate allergic response. Deficits in Treg cells or their localization to mucosa have been implicated in asthma and atopic dermatitis.[30] Attempts have been made to reduce hypersensitivity reactions by oral tolerance and other means of repeated exposure. Repeated administration of the allergen in slowly increasing doses, subcutaneously or sublingually appears to be effective for allergic rhinitis.[31] Repeated administration of antibiotics, which can form haptens to cause allergic reactions, can also reduce antibiotic allergies in children.[32]

The tumor microenvironment

Immune tolerance is an important means by which growing tumors, which have mutated proteins and altered antigen expression, prevent elimination by the host immune system. It is well recognized that tumors are a complex and dynamic population of cells composed of transformed cells as well as stromal cells, blood vessels, tissue macrophages, and other immune infiltrates.[9][33] These cells and their interactions all contribute to the changing tumor microenvironment, which the tumor largely manipulates to be immunotolerant so as to avoid elimination. There is an accumulation of metabolic enzymes that suppress T cell proliferation and activation, including IDO and arginase, and high expression of tolerance-inducing ligands like FasL, PD-1, CTLA-4, and B7.[9][22] Pharmacologic monoclonal antibodies targeted against some of these ligands has been effective in treating cancer.[34] Tumor-derived vesicles known as exosomes have also been implicated promoting differentiation of iTreg cells and myeloid derived suppressor cells (MDSCs), which also induce peripheral tolerance.[9][35] In addition to promoting immune tolerance, other aspects of the microenvironment aid in immune evasion and induction of tumor-promoting inflammation.

Evolution

Though the exact evolutionary rationale behind the development of immunological tolerance is not completely known, it is thought to allow organisms to adapt to antigenic stimuli that will consistently be present instead of expending considerable resources fighting it off repeatedly. Tolerance in general can be thought of as an alternative defense strategy that focuses on minimizing impact of an invader on host fitness, instead of on destroying and eliminating the invader.[36] Such efforts may have a prohibitive cost on host fitness. In plants, where the concept was originally used, tolerance is defined as a reaction norm of host fitness over a range of parasite burdens, and can be measured from the slope of the line fitting these data.[37] Immune tolerance may constitute one aspect of this defense strategy, though other types of tissue tolerance have been described.[36]

Schematic of the reaction norm of tolerance (after[37]). Organisms of genotype 2 are considered more tolerant to the pathogen than organisms of genotype 1.

The advantages of immune tolerance, in particular, may be seen in experiments with mice infected with malaria, in which more tolerant mice have higher fitness at greater pathogen burdens. In addition, development of immune tolerance would have allowed organisms to reap the benefits of having a robust commensal microbiome, such as increased nutrient absorption and decreased colonization by pathogenic bacteria.

Though it seems that the existence of tolerance is mostly adaptive, allowing an adjustment of the immune response to a level appropriate for the given stressor, it comes with important evolutionary disadvantages. Some infectious microbes take advantage of existing mechanisms of tolerance to avoid detection and/or elimination by the host immune system. Induction of regulatory T cells, for instance, has been noted in infections with Helicobacter pylori, Listeria monocytogenes, Brugia malayi, and other worms and parasites.[8] Another important disadvantage of the existence of tolerance may be susceptibility to cancer progression. Treg cells inhibit anti-tumor NK cells.[38] The injection of Treg cells specific for a tumor antigen also can reverse experimentally-mediated tumor rejection based on that same antigen.[39] The prior existence of immune tolerance mechanisms due to selection for its fitness benefits facilitates its utilization in tumor growth.

Tradeoffs between immune tolerance and resistance

Immune tolerance contrasts with resistance. Upon exposure to a foreign antigen, either the antigen is eliminated by the standard immune response (resistance), or the immune system adapts to the pathogen, promoting immune tolerance instead.

Resistance typically protects the host at the expense of the parasite, while tolerance reduces harm to the host without having any direct negative effects on the parasite.[37] Each strategy has its unique costs and benefits for host fitness:[36]

Costs Benefits
Elimination (resistance)
  • Pain, swelling, and disruption of tissue function by inflammation.
  • Tissue damage by inflammatory mediators (immunopathology)
  • High energy cost
  • Risk of autoimmunity, hypersensitivity, allergy
  • Reduces pathogen burden
  • Neutralizes toxins and eliminates dangerous organisms
  • Prevents parasitism
Tolerance
  • Direct damage by pathogen (toxins, digestion, etc.)
  • Energy and resources lost to pathogen
  • Reduced tissue damage from immune response
  • Less selection pressure on pathogens for resistance
  • Promotes commensalism
  • Lower energy cost

Evolution works to optimize host fitness, so whether elimination or tolerance occurs depends on which would benefit the organism most in a given scenario. If the antigen is from a rare, dangerous invader, the costs of tolerating its presence are high and it is more beneficial to the host to eliminate it. Conversely, if experience (of the organism or its ancestors) has shown that the antigen is innocuous, then it would be more beneficial to tolerate the presence of the antigen rather than pay the costs of inflammation.

Despite having mechanisms for both immune resistance and tolerance, any one organism may be overall more skewed toward a tolerant or resistant phenotype depending on individual variation in both traits due to genetic and environmental factors.[37] In mice infected with malaria, different genetic strains of mice fall neatly along a spectrum of being more tolerant but less resistant or more resistant but less tolerant.[40] Patients with autoimmune diseases also often have a unique gene signature and certain environmental risk factors that predispose them to disease.[2] This may have implications for current efforts to identify why certain individuals may be disposed to or protected against autoimmunity, allergy, inflammatory bowel disease, and other such diseases.

참고 문헌

  1. ↑ 가 나 다 라 마 바 사 Medawar, Peter (1960년 12월 12일). “Nobel Lecture: Immunological Tolerance”. 《The Nobel Prize》. 2020년 7월 24일에 확인함. 
  2. ↑ 가 나 다 라 마 바 사 아 Murphy, Kenneth (2012). 《Janeway's Immunobiology: 8th ed.》. Chapter 15: Garland Science. 611–668쪽. ISBN 0815342438. 
  3. ↑ Choi, J; Kim ST; Craft J (Dec 2012). “The pathogenesis of systemic lupus erythematosus-an update.”. 《Curr Opin Immunol》 24 (6): 651–657. doi:10.1016/j.coi.2012.10.004. PMC 3508331. PMID 23131610. 
  4. ↑ 가 나 다 Round, JL; O'Connell RM; Mazmanian SK (May 2010). “Coordination of tolerogenic immune responses by the commensal microbiota”. 《J Autoimmun》 34 (3): J220-J225. doi:10.1016/j.jaut.2009.11.007. PMC 3155383. PMID 19963349. 
  5. ↑ Perniola, R (2012). “Expression of the autoimmune regulator gene and its relevance to the mechanisms of central and peripheral tolerance.”. 《Clin Dev Immunol》 2012: 207403. doi:10.1155/2012/207403. PMC 3485510. PMID 23125865. 
  6. ↑ Verbsky, JW; Chatila TA. (Dec 2013). “Immune dysregulation, polyendocrinopathy, enteropathy X-linked (IPEX) and IPEX-related disorders: an evolving web of heritable autoimmune diseases”. 《Curr Opin Pediatr》 25 (6): 708–714. doi:10.1097/mop.0000000000000029. PMC 4047515. PMID 24240290. 
  7. ↑ Maazi, H; Lam J; Lombardi V; Akbari O (Jun 2013). “Role of plasmacytoid dendritic cell subsets in allergic asthma”. 《Allergy》 68 (6): 695–701. doi:10.1111/all.12166. PMC 3693732. PMID 23662841. 
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  16. ↑ Sprent, J; Kishimoto H (2001). “The thymus and central tolerance”. 《Philos Trans R Soc Lond B Biol Sci》 356 (1409): 609–616. doi:10.1098/rstb.2001.0846. PMC 1088448. PMID 11375064. 
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