2016 Group 5 Project

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Mast Cell

Mastcellbanner.jpg

Introduction

Mast cells are immune cells that are of haematopoietic lineage traditionally thought to only play a role in pathogen surveillance, however, studies of the interactions between host and parasite have illuminated another role, that being one of protection. [1][2] The major role of mast cells in pathogen recognition is supported by their location in host peripheral tissues that commonly come into contact with pathogens, such as skin, mucosal membranes of the respiratory system and even the gastrointestinal tract. Their location at the host-environment interface allows them to proliferate in response to appropriate stimulus and communicate the presence of pathogens to the lymph nodes and other immune cells. [3] [4] Mast cells are highly granulated which typically contain proteases, particularly tryptase and chymase, that are influenced and regulated by the presence of cell mediators such as Interleukin-4. [5] Armed with these preformed granules, mast cells can alter their phenotype depending on their environment, demonstrated by selective cytokine production and the altering of transcription processes and storage of preformed mediators. [6] [7] The presence of preformed granules allows mast cells to respond quickly to pathogen invasion, establishing their major role in the immediate phase of response to allergic pathogens. Mast cells are best known for their role in allergic disease such as asthma, eczema and allergic rhinitis, where degranulation occurs, releasing mediators such as histamine and promoting the acute inflammatory response. [8]

History

(unfinished)- still working on it!

Year Finding
1878 Mast cells are first identified and named ‘Mastzellen’ by Paul Ehrlich in his doctoral thesis at Leipzig University, Germany. Ehrich described these Mastzellen as being often associated with nerves, blood vessels and glandular ducts. [9]
1894 German physician Paul Gerson Unna described mast cells in association with pathology. He noted that the cutaneous lesions called urticarial pigmentosa (UP) were accompanied with an increased number of mast cells below the lesions.[10]
1900 Mast cells are thought to originate from myeloid stem cells. [11]
1939 Erik J. Jorpes identified Mast cells as carriers of heparin. [12]
1953 JF Riley described Mast cells as containing histamine. [13]
Late 1950s Mast cells are understood to play an important role in anaphylaxis.[14]
1960 Mast cells are known to have trypsin-like esterase activity,[15]these enzymes are later called tryptase. [16]
1989 Plaut and Wodnar –Filipowicz separately discovered that mast cells produce and release IL-3, IL-4, IL-5, IL-6, and GM-CSF. [17] [18]
1990 Mast cells are found to be a source of TNF-α. .[19]
1996 Mast cells are seen as contributors to innate immunity.[20]
2003 Mast cells are understood to release growth factors and affect angiogenesis, which contributes to tumour progression.[21]
2006 It is understood that there is a relationship between regulatory T cells and mast cells
2007

Physiology

Morphology

receptors, microscopy

Function

multifunctional purpose

Origin and Migration

figure_: Most of the haematopoetic lineages are rather well understood, however there is still a lot of uncertainty in the mast cell ontogenesis. Acronyms: MPP: MultiPotent Progenitor, HSC: Haematopoetic Stem Cell, CLPs: Common Lymphoid Progenitors, CMP: Common Myeloid Progenitors, GMP: Granulocyte-Macrophage Progenitor, MEP: Megakaryocyte–Erythrocyte Progenitor


Mast cells have a hematopoietic origin from the bone marrow. This was first shown when a patient suffering from acute myeloid leukaemia underwent an allogeneic bone marrow transplant and after 198 days post transplant mast cells were found. The researchers used Polymerase Chain Reaction to show that the mast cells being generated by the recipient showed the donor’s genotype, meaning the donors bone marrow was the origin of the Mast Cels [22]


Committed mast cell precursors are found in the bone marrow. This was shown in murine studies by using mast cell specific antibodies to separate them out immunomagnetically. These precursors had mRNA present for some subunits of FCeR1, the receptor that is characteristic of mast cells, but did not express the receptor on their surface. As a result they are considered the precursor cells. They also contained mRNA for mast cell specific proteases. [23].


File:Mast cell origin and migration.jpg
Mast cell precursors derive from the myeloid progenitor cells in the bonemarrow. mast cell precursor cells then go into the ciruclation and migrate into different tissues depending on adhesin expression. Acronyms: MPP: MultiPotent Progenitor, MCP: Mast Cell Commited Progenitor, CLP: Common Lymphoid Progenitor, CMP: common myeloid progenitor


As stated above research suggests in adults mast cells are produced from haematopoietic origins by a committed precursor in the bone marrow. However in rat embryos, using similar immunological methods, it has been shown that embryonic mast cells mature in the aorta-gonad-meso-nephros region (AGM) which indicates that in human embryos mast cells may develop outside of the bone marrow [24]


Interestingly, mast cell precursors do not differentiate into mast cells in the bone marrow, their precursor cells travel to extramedullary sites with good vasculature such as connective region of the skin or mucosa of the GIT before differentiation.[25]


The migration of mast cell precursors is tissue specific. It depends on the interaction of the mast cell precursors's integrins binding to the corresponding adhesion molecules in different tissues. For example in the mucosa the adhesin MAdCAM-1 binds to the mast cell precursor's integrins[26]. The precursors also express chemokine receptors that may play a role in migration [27]


Differentiation

There are both intrinsic and extrinsic factors that stimulate mast cell differentiation from haematopoetic stem cells. The following have been discovered in vitro cell lines from mice that have specific genetic mutations.

Extrinsic and Intrinsic factors influencing Mast Cell Development In Vitro
Intrinsic Extrinsic
Growth Factor Stem Cell Factor that acts on KIT receptor, has been shown to stimulate mast cell differentiation in vitro [28] . There are also growth factors that inhibit mastopoesis such as thrombopoetin, which acts by down-regulating GATA1 [29] Transcription factor MitF - Involved in c-kit expression that influences mast cell specific protease expression[30]
IL-3 from induced T cells as a result of external stimuli[31] i.e. parasitic infection. It has been shown to be responsible for Mast Cell survival, development and maturation in vitro [32] but has to be used synergistically with IL-3[33] Transcription factors Gata2 and Gata1[34] - Expressed throughout differentiation in vitro. Studies have shown that mutations in GATA1 gene cause defects at all stages of differentiation of mast cell development [35]


~


Activation

Figure 1: Activation and simplified signalling pathways After activation of the FceR1 by cross-linking(only one shown in diagram), LYN and SYK phosphorylate LAT. LAT then activates cytosolic adaptor molecules and through phosphorylation cascades MAPK pathway is initiated, and/or cytosolic calcium ion concentrations are increased. The former results in either the activation of phospholipase A2 (PLA2) which begins eicosanoid synthesis or directly interacts with transcription factors to influence cytokine production. An increase in Ca ion triggers cytoskeletal changes that result in degranulation of the mast cell.

Activation occurs when two mast cell FceR1 receptors crosslink after antigen binding. Receptor coupling factors such as LYN and SYK phosphorylate other proteins[36] and downstream effects include either:

1) Eicosanoid production: if the MAPK pathway is activated[37]

2) Cytokine production: if Transcription factors are activated by MAPK pathway[38]

3) Degranulation: if intracellular Calcium increases as a result of the phosphorylation cascade[39]

Mediators

Mast cells produce an array of bioactive molecules. These are released either by vesicular exocytosis or de novo synthesised and secreted through membrane channels. Moon et al.(2014)[40] performed a review of the literature and showed the major stored mediators in one table (see figure _) and the de novo synthesised mediators (see figure__).

Stored Mediators These mediators are stored in vesicles and are usually proteins such as amines, cytokines, or enzymes [41]. These may be mixed in vesicles i.e. b-hexoaminidase and heparine can both be secreted together (heterogenic secretion) or not. Morphometric research shows that the granules that contain mediators result from the fusion of smaller granules (called progranules) that fuse together to form mature granules under regulation of RabGTPases. This has been shown by mutations of RabGTPases gene significantly affecting granule size [42]. The fusion of granules is compartmentalised. Progranules form out of the golgi apparatus and maturation may occur

finish this paragraph with ref^^
Stored Mast Cell Mediators

Table 1 mediators mast cell.PNG

de novo synthesised mediators Lipid mediators are de novo synthesised from several locations in the cell. Research suggests eicosanoid lipid mediators can be produced in the membrane of Endoplasmic reticuli, nuclear membranes or lipid bodies [43]. They are made via oxidation reactions of long chain fatty acids. These oxidised fatty acids can then take one of two pathways depending on which enzyme acts on them next. The lipoxygenase pathway produces mostly leukotrienes from arachidonic acid and the cyclooxygenase pathway produces prostaglandins. These molecules are involved in inflammation and do not diffuse freely across the membrane due to their negative charge at physiological pH. As such, they are secreted via transporters [44].

de novo eicosanoid production

File:Eicosanoid pathway.GIF

Degranulation

Electron microscopy ultrastructural research suggests that these granules may be secreted in 2 ways:

DEGRANULATION MECHANISMS
Piecemeal Degranulation Anaphylactic Degranulation
- The process where only fragments of vesicles are selectively released without membrane to membrane fusion, the mechanism is rather poorly understood, which involves a pleiomorphic tubular structure that allows a for granule stored proteins to be secreted selectively [45] - Involves the full exocytosis of granule or vesicle as a result of membrane to membrane fusion
- Stimulated by Toll-like Receptor activation [46] and interactions with T regulatory cells [47] among other situations [48] - Stimulation is FceR1 cross-linking [49]
- SNARES protein mediated(defined in glossary)




~


Pathology

Mast Cell Roles in the Host Defense[50]

Mast cells are sentinel cells that are found distributed within the connective tissue throughout the body and play an important role in both acute and chronic inflammation. Mast cells that are coated with IgE antibodies specific for certain environmental antigens are triggered to release histamine and other cytokines that induce early vascular changes that are hallmarks of acute inflammation. [51] The immediate responsibility of mast cells is to recognise that infection by a pathogen has occurred, which is achieved by direct recognition of the pathogen by pattern recognition receptors that are activated in response to pathogen-associated molecular patterns (PAMPs). [52] A study conducted by Supajatura et al. demonstrated that the activation of different toll-like receptors (TLR2 or TLR4) by varying PAMPs resulted in differential activation of mast cells evident in lypopolysaccharide stimulation of TLR4 resulting in cytokine release compared to peptidoglycan stimulation of TLR2 receptors resulting in both degranulation and cytokine production.[52] However, mast cells can also act directly on pathogens through the production of reactive oxygen species and phagocytosis, as demonstrated by the engulfing of Fim-H expressing enterobacteria. [53]

Mast cells also play a major role in atopic diseases such as asthma, eczema, anaphylaxis and allergic rhinitis. The basis of these allergic diseases is the activation and binding of the high-affinity immunoglobulin E (IgE) receptor FceR1 to initiate receptor clustering and release of mediators, a signalling network dependent on the strength and type of stimulus. [54] These downstream signal transduction events involve tyrosine phosphorylation which induces the degranulation of mast cells and cytokine and lipid mediator secretion. [55] Furthermore, similarly to neutrophils, mast cells have been seen to produce extracellular traps through the utilisation of the cathelicidin LL-37, histones and tryptase. [56] These three products of mast cells form the structural foundation of the extracellular traps, demonstrated to trap the bacteria S. pyogenes when in close proximity in co-culture in vitro. [56]

Mast Cell Activation Disease

Mast Cell activation disease describes a group of diseases or disorders that are characterised by the accumulation of mast cells in the bone marrow and/or other extracutaneous organs and tissues, and/or the abnormal release of different mast cell mediators. [57] The three main subsets of MCAD are mast cell activation syndrome (MCAS), systemic mastocytosis (SM); including aggressive systemic mastocytosis and isolated bone marrow mastocytosis; and mast cell leukemia (MCL). [58] The World Health Organisation (WHO) have defined SM and MCL as truly rare diseases as defined by their criteria, however, it has been suggested that MCAS is more common. [59] It has also been suggested that pathological mast cells play an important role in the pathogenesis of SM and MCAS, as well as the development of idiopathic anaphylaxis. [60] [61]

Pathogenesis

Mutations in enzymes, kinases and receptors that are necessary for mast cell activity regulation and essential in the establishment of a clonal cell population have been implicated as important factors in the pathogenesis of MCAD's, particularly two or more alteration in the tyrosine kinase Kit.[62] The tyrosine kinase Kit mutation occurs at the codon 816 which has been linked with not only good prognosis of SM and conversely advancement of the disease, but also has been identified in healthy subjects, suggesting that there are number of external factors contributing to the pathogenesis. [63] [64] Further genetic findings suggest that all three subsets of MCAD are clinical manifestations that share one common genetic root associated with mast cell dysfunctions. [65] [62]

The below table lists the criteria for a diagnosis of Mast Cell Activation Syndrome and Systemic Mastocytosis. It has been adapted from the table published in the review Mast cell activation disease: a concise practical guide for diagnostic workup and therapeutic options [66] with original reference to the criteria established by WHO. [59]

Criteria Mast Cell Activation Syndrome Systemic Mastocytosis
Major Criteria 1. Presence of pathological mast cells in bone marrow biopsies and/or sections of other extracutaneous organs (multifocal and disseminated).

2. Mast cell mediator release syndrome; characterised by a unique list of clinical complaints e.g. skin lesions, lymphadenopathy and elevated levels of histamine and heparin in the blood.

Aggregates of >15 mast cells in bone biopsies and/or sections of other extracutaneous organs.
Minor Criteria 1. Abnormal morphology of mast cells in bone marrow biopsies and/or sections of other extracutaneous organs. Abnormal morphology includes spindle shaped morphology or expression of CD25 on mast cell surfaces. [59]

2. Mast cell expression of CD2 and/or CD25 in the bone marrow.

3. Proven increased activity of mast cells detected with genetic changes within mast cells located in the blood, bone marrow and extracutaneous organs.

4. Increase in the content of:

  • tryptase in the blood
  • N-methylhistamine in the urine
  • heparin in the blood
  • chromogranin A in the blood
  • other mast cell mediators
1. Abnormal morphology of mast cells in bone marrow biopsies and/or sections of other extracutaneous organs. Abnormal morphology includes spindle shaped morphology or expression of CD25 on mast cell surfaces. [59]

2. Mast cell expression of CD2 and/or CD25 in the bone marrow.

3. Mutation of codon 816 in tyrosine kinase Kit.

4. Serum total tryptase >20 ng/ml.

Clinical Manifestations

A patient is initially suspected of having MCAD's based upon a diagnosis of symptoms associated with the over production of mast cell mediators and the identification of skin lesions. However, due to the distribution of mast cells and the heterogeneity of their mediators, clinical symptoms vary greatly between individuals and can affect any organ or tissue. [67] Some common signs and symptoms are listed below.

Typical Signs and Symptoms associated with unregulated release of mast cell mediators

Typical Signs and Symptoms associated with unregulated release of mast cell mediators[68]

Treatment

There is no curative therapy for patients diagnosed with MCAD's, however effective drug treatments need to be individually tailored, considering the individuals signs, symptoms, complications and drug tolerances. Similarly to the treatment of all disease, avoidance of environmental irritants and reduced exposure to identifiable triggers of mast cell degranulation such as certain medication, animals venoms and animal furs, is an important element of treatment of MCAD's. [69] Studies had shown that patients diagnosed with SM and treated with kinase inhibitors partially improved clinical symptoms associated with mast cell mediators, as well as normalised mast cell infiltration observed in bone marrow specimens. [70] [71]

The following table lists some common treatments for MCAD's. It has been adapted from the table published in the review paper Mast cell activation disease: a concise practical guide for diagnostic workup and therapeutic options. [72]

Type Of Therapy Treatment Options
Basic Therapy: Oral combination therapy aimed to reduce release of mast cell activity
  • H1-histamine receptor antagonist: actively block H1-histamine receptors on mast cells and therefore alleviate associated symptoms
  • H2-histamine receptor antagonist: actively block H2-histamine receptors on mast cells and therefore alleviate associated symptoms
  • Cromolyn sodium: stabilising mast cells
  • Slow release Vitamin C: inhibits mast cell degranulation and increases histamine degradation
  • Ketotifen: blocks activation of H1-histamine receptors on mast cells and stabilises mast cells
Systemic Therapies: Taken orally as needed to reduce systemic symptoms
  • Headaches = Paracetamol
  • Nausea = metoclopramide; dimenhydrinate; 5-HT3 receptor inhibitors
  • Gastric complaints = proton pump inhibitors
  • Osteoporosis, Osteolysis and/or bone pain = biphosphonates
  • Conjunctivitis = preservative-free eye drops with glucocorticoids for brief courses
  • Non-cardiac chest pain = additional dose of a H2-histamine receptor antagonist and proton pump inhibitors to release any gastroesophageal reflux

Parathyroid bone disease

(draft)

An increased number of mast cells in the bone marrow can be linked with parathyroid bone disease, most common of which being chronic hyperparathyroidism (HPT). Those suffering from HPT have a disturbed immune function, and mast cells play a major role in innate immunity. Parathyroid hormone (PTH) significantly increases the number of mast cells in those with HPT. There is a 5-fold increase in bone marrow mast cells in those with HPT as compared to the controls. [73] Elevated levels of PTH increase migration of preoestoblastic fibroblasts to the bone surface, and while these generally differentiate into osteoblasts, the increased PTH levels cause terminal differentiation to be impaired. The accumulation of mast cells on bone surfaces as a response to elevated PTH levels lead to this PTH-induced peritrabcular fibrosis, and cause the excessive recruitment of fibroblasts on bone surfaces. [73] An increase in kit- ligand expression causes the build up of mast cells, as it is a potent chemotactic factor for these mast cells. Combined with an increased PDFG-A gene expression, these peritrabcular mast cells promote fibrosis, ultimately leading to bone disease. [73]


Allergic Rhinitis

Allergic Rhinitis is one of the most prevalent atopic diseases affecting approximately 400 million people world wide and is associated with reduced productivity, reduced quality of life and a lower learning performance in schools. [74] [75] Allergic Rhinitis is a disease that affects the mucosal membrane of the nose and is mediated by Immunoglobulin E (IgE), a product of mast cells. The complex interplay between immune system and an allergen results in the release chemokines, cytokines and mediators (such as histamine release by mast cells) leads to clinical manifestations including nasal blockage, sneezing and allergic conjunctivitis.[76]

Pathogenesis

Similarly to all allergic diseases, Allergic Rhinitis can be divided into an immediate phase and a late phase. The immediate phase, occurring within minutes of exposure to the allergen, is characterised by mast cell degranulation, release of pre-formed and newly formed mediators (such as histamine) stimulating the nerve endings of the trigeminal nerve (CN5) and inducing sneezing.[77] The late phase response, occurring 4-6 hours after antigen stimulation, is driven by mast cell release of chemokines including IL-4 and IL-13, which upregulates the expression of adhesion molecules on endothelial cells resulting in an increased infiltration of immune cells (eosinophils, basophils, etc.) into the nasal mucosa. [78] Mast cells have been found to further contribute to the late phase through the histamine-tyrptase induced upregulation of granulocytemacrophage colony stimulating factor and the chemokine RANTES in nasal epithelial cells. [79]

Asthma

Asthma is an allergic disease significantly characterised by variable airflow obstruction as well as airway hyper responsiveness. [80] It causes repeated episodes of wheezing, tightness in chest, breathlessness, as well as coughing during night or early morning. There has been a significant increase of asthma incidence in the West over the past four decades. [81]

Pathogenesis

Asthma occurs through the accumulation of eosinophils, CD4+ lymphocytes in the submucosa, as well as mucous gland hyperplasia and mast cell degranulation. [82]. IL-18, a proinflammatory cytokine promotes the production of type 2 helper T cells, which allows for most of the features of the disease, including IL-13 promoting IgE production. [83] [84]This coats the submucosal mast cells, which when exposed to the allergen, release the granule contents. [85] This subsequently leads to the induction of a two wave reaction – the early phase and late phase reaction, in which the early phase is characterised by bronchoconstriction and increased mucus production, and the late stage responses involves inflammation through activation of eosinophils, neutrophils and T cells. [86]

Mast cells are found to be localised in the airway smooth muscle, and the subsequent interaction between mast cells and the smooth muscle cells is an important factor in the occurrence of asthma, due to the fact that the smooth muscle provides the appropriate microenvironment for the differentiation, activation and survival of mast cells. [87]

Eczema

(draft)

Atopic dermatitis, or eczema, is a chronic pruritic inflammatory skin disease [88] characterised by high Immunoglobulin E (IgE) responsiveness. [89] While the aetiology of the disease is not fully understood, it is caused due to a interaction between environmental and genetic factors, particularly involving high levels of IgE. [88] IgE is produced in response to common antigens, and is bound to the surface of mast cells, [89] which infiltrate the skin lesions of the disease. [88]. Thus, an accumulation of mast cells is required for maximum skin inflammation during eczema. [88] The IgE proceeds to bind to FceRI, and consequently has a positive effect on mast cell survival and activation.[88]

In eczema, the impaired skin barriers allow allergens easy access into the dermal and epidermal layers. The allergens are taken up by Langerhans cells, and these cells mature in order to present the allergens to helper T cells in the lymph nodes. Activated Th2 cells migrate once again to the skin sites that are re-exposed to the allergens, and subsequently recruit mast cells which cause the characteristic tissue damage and irritation of eczema. [88]

Mast cell chymase (MCC) is also involved in this condition, and is a serine protease which accumulates in the dermis of the skin. An increase in MCC promotes skin inflammation and eczema. The polymorphism of MCC is significantly associated with the occurrence of eczema, and different variations of this MCC is one source of genetic risk for the condition. [89]

Future Research

- (For pathology- eczema): The precise aetiology of eczema and the role of mast cells in this process is not completely understood, but current research indicates that it is multifactorial, and the disease arises from intricate interactions between genetic and environmental factors [88]. There is still ongoing research in this field.

Reviews

Glossary

Atopy: predisposition to developing IgE associated allergic diseases.

Atopic disease: a clinical condition caused by an allergy

Allergic Rhinitis: commonly known as hay fever

Immunoglobulin E (IgE):antibodies produced by the body's immune system

FceR1: high affinity Immunoglobulin E receptor

  1. <pubmed>6504156</pubmed>
  2. <pubmed>3897955</pubmed>
  3. <pubmed>15840693</pubmed>
  4. <pubmed>14595438</pubmed>
  5. <pubmed>9414284</pubmed>
  6. <pubmed>18424663</pubmed>
  7. <pubmed>7089960</pubmed>
  8. <pubmed>20498670</pubmed>
  9. Ehrlich, P. (1878) Beitra¨ge zur Theorie und Praxis der Histologischen Fa¨rbung. Thesis, Leipzig University.
  10. Unna PG. Die spezifische färbung der mastzellenkörnung. Monatsh Prakt Dermatol. 1894;19:367–368.
  11. Jolly, M.J. (1900) Clasmatocytes et mastzellen. Compte Rendus Socie´te´ de Biologie (Paris), 52, 437–455.
  12. Jorpes JE. The site of formation of heparin. In: Jorpes JE, editor. Heparin: Its Chemistry, Physiology, and Application in Medicine. London, United Kingdom: Humphrey Milford (Oxford Univ Press); 1939. pp. 30–39.
  13. <pubmed>PMC1366001</pubmed>
  14. <pubmed>13685195</pubmed>
  15. <pubmed>13828452</pubmed>
  16. <pubmed>7028744</pubmed>
  17. <pubmed>2469965</pubmed>
  18. <pubmed>2524008</pubmed>
  19. <pubmed>2374592</pubmed>
  20. <pubmed>10047539</pubmed>
  21. <pubmed>12660426</pubmed>
  22. <pubmed>7949167</pubmed>
  23. <pubmed>15718418</pubmed>
  24. <pubmed>23505443</pubmed>
  25. <pubmed>17468237</pubmed>
  26. <pubmed>11696590</pubmed>
  27. <pubmed>15705791</pubmed>
  28. <pubmed>7524746</pubmed>
  29. <pubmed>17468237</pubmed>
  30. <pubmed>18839840</pubmed>
  31. <pubmed>7524746</pubmed>
  32. <pubmed>3002522</pubmed>
  33. <pubmed>7524746</pubmed>
  34. <pubmed>8562971</pubmed>
  35. <pubmed>12566412</pubmed>
  36. <pubmed>16470226</pubmed>
  37. <pubmed>16470226</pubmed>
  38. <pubmed>16470226</pubmed>
  39. <pubmed>16470226</pubmed>
  40. <pubmed>25452755</pubmed>
  41. <pubmed>25452755</pubmed>
  42. <pubmed>24696234</pubmed>
  43. <pubmed>1219072</pubmed>
  44. <pubmed>9506966</pubmed>
  45. <pubmed>20712018</pubmed>
  46. <pubmed>12574323</pubmed>
  47. <pubmed>21509780</pubmed>
  48. <pubmed>4231949</pubmed>
  49. <pubmed>1483068</pubmed>
  50. <pubmed>22577358</pubmed>
  51. Robins Basic Pathology Kumar, Vanay; Abbas, Abul K.; Aster, Jon C., Philadelphia: Elsevier Saunders., 2013
  52. 52.0 52.1 <pubmed>12021251</pubmed>
  53. <pubmed>8120397</pubmed>
  54. <pubmed>12782712</pubmed>
  55. <pubmed>12089510</pubmed>
  56. 56.0 56.1 <pubmed>18182576</pubmed>
  57. <pubmed>21035176</pubmed>
  58. <pubmed>20824412</pubmed>
  59. 59.0 59.1 59.2 59.3 <pubmed>11377686</pubmed>
  60. <pubmed>17638853</pubmed>
  61. <pubmed>17883734</pubmed>
  62. 62.0 62.1 <pubmed>17710669</pubmed>
  63. <pubmed>16741248</pubmed>
  64. <pubmed>15790486</pubmed>
  65. <pubmed>18509466</pubmed>
  66. <pubmed>21418662</pubmed>
  67. <pubmed>18662284</pubmed>
  68. <pubmed>21418662</pubmed>
  69. <pubmed>20855864</pubmed>
  70. <pubmed>19193436</pubmed>
  71. <pubmed>16779792</pubmed>
  72. <pubmed>21418662</pubmed>
  73. 73.0 73.1 73.2 <pubmed>20200965</pubmed>
  74. <pubmed>9553981</pubmed>
  75. <pubmed>10570499</pubmed>
  76. Robins Basic Pathology Kumar, Vanay; Abbas, Abul K.; Aster, Jon C., Philadelphia: Elsevier Saunders., 2013
  77. Robins Basic Pathology Kumar, Vanay; Abbas, Abul K.; Aster, Jon C., Philadelphia: Elsevier Saunders., 2013
  78. <pubmed>8376806</pubmed>
  79. <pubmed>10925308</pubmed>
  80. <pubmed>12037149</pubmed>
  81. Robins Basic Pathology Kumar, Vanay; Abbas, Abul K.; Aster, Jon C., Philadelphia: Elsevier Saunders., 2013
  82. <pubmed>12037149</pubmed>
  83. <pubmed>12037149</pubmed>
  84. <pubmed>27069315</pubmed>
  85. Robins Basic Pathology Kumar, Vanay; Abbas, Abul K.; Aster, Jon C., Philadelphia: Elsevier Saunders., 2013
  86. Robins Basic Pathology Kumar, Vanay; Abbas, Abul K.; Aster, Jon C., Philadelphia: Elsevier Saunders., 2013
  87. <pubmed>12037149</pubmed>
  88. 88.0 88.1 88.2 88.3 88.4 88.5 88.6 <pubmed>23752044</pubmed>
  89. 89.0 89.1 89.2 <pubmed>8774571</pubmed>