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Pharm immuno3 &4 q innate immunity & complement
- 1. LECOM-Pharmacy School Immunology 3 & 4 Dr. Saber Hussein Innate Immunity & Complement
- 6. Cytokines of Innate Immunity
- 14. Innate & Adaptive Immunity
- 20. Leukocytes extravasation Blood vessel Infected tissue
- 21. Complement Alternative Pathway Classic Pathway
- 33. Complement Classic Pathway Alternative Pathway Common Pathway
- 34. MAC & Cell Lysis
- 35. Activities of complement fragments Split Products and Their Activity
Hinweis der Redaktion
- TNF: FEVER STIMULATE RECRUITMENT OF NEUTROPHILS AND MACROPHAGE STIMULATES CHEMOKINE PRODUCTION BY ENDOTHELIALS AND MACROPHAGE ADHESION MOLECULES CACHEXIA
- WOUND IMMUNE FUNCTION IS ACCELERATED BY LEUKOCYTE SECRETION OF TNF-á , IL-1 â , IL-2, AND IL-6 AFTER EXPOSURE TO SUBSTANCE P A. V. Delgado*, A. T. McManus US Army Institute of Surgical Research Fort Sam Houston, Texas, 78234 J. P. Chambers University of Texas at San Antonio San Antonio, Texas, 78249 SUMMARY The military has traditionally been on the forefront of trauma research in the world. In the scope of military applications, the management of wounds and wound-associated pain is a key task for the combat medic. In the combat environment the medic may be called upon to deal with multiple casualties simultaneously. Improved methods for wound care and pain management will enable the medic to focus more time on the most seriously wounded while enabling other wounded casualties to defend themselves and or participate in self-care. In a combat situation, the time to evacuation to a higher level of care may be hours to days. New methods are needed to provide for longer-term pre-evacuation wound care. The interaction between components of the nervous system and multiple target cells of the cutaneous immune system has received increased attention. Recently, neuropeptides have been shown to play an important role in the inflammatory cascade. Neuropeptides such as substance P (SP) are released by cutaneous neurons and modulate the function of immunocompetent and inflammatory cells as well as epithelial and endothelial cells. SP has been shown to function as a mediator for cell proliferation, cytokine production, and upregulation of various cell surface receptors. SP has been extensively studied as the mainstream neuropeptide of the more than fifty known neuroactive molecules. The understanding of SP has evolved since the original concept as pain transmitter in the dorsal horn. Seventy years of research have lead to the current understanding of the diverse functions of this neuropeptide. With all the research conducted on this neuropeptide, there are still questions unanswered about the different roles of SP and its involvement in various physiological systems, especially in tissue repair as a result of trauma. Our interest is on the involvement of SP as an integral part of the interaction between the nervous and the immune systems. We would like to address how the peripheral nervous system (PNS), acting through neuropeptides such as SP, not only relays sensory information to the central nervous system (CNS) but also plays an effector role in the inflammatory, proliferative, and reparative processes after injury. There is evidence in the literature that neurogenic stimuli affects cellular events that are involved in inflammation, proliferation, and the extracellular matrix, as well as cytokine and growth factor synthesis. Four of the most common pro-inflammatory cytokines are TNF- α , IL-1 β , IL-2, and IL-6. These cytokines are involved in a variety of immunological functions as well as various target cells. IL-6 has been shown to promote terminal differentiation of proliferating B cells into plasma cells, stimulates antibody secretion, and induces synthesis of acute-phase proteins. IL-6 is mainly secreted by monocytes and macrophages. This cytokine is always found in increased levels in sites of inflammation and is likely very important in a number of undescribed ways in inflammatory regulation. IL-2 is predominantly secreted by T-cells and has been shown to have proliferative effects as well as enhancing activity of natural killer (NK) cells. IL-1 β is an important part of the inflammatory response. An inflammation associated function of IL-1 β is its action on receptors on endothelial cells within the CNS and appears to 'reset' the thermoregulatory centre increasing the core body temperature causing fever. IL-1 β co-stimulates activation of T-cells, promotes maturation of B-cells, enhances NK activity, increases adhesion molecules expression, and acts as a chemotactic attractant. Cells that have been shown to secrete IL-1 β are monocytes, macrophages, B-cells, dendritic cells, endothelial cells, neutrophils, and hepatocytes. TNF- α is secreted by macrophages and mast cells and has been shown to have cytotoxic properties to tumor cells and has been associated with chronic inflammation. TNF- α is has been associated with the induction of apoptosis through NF-kB. This protein is reported to be a major immune response-modifying cytokine produced primarily by activated macrophages. TNF- α induces the expression of other autocrine growth factors, increases cellular responsiveness to growth factors and induces signaling pathways that lead to proliferation. TNF- α acts
- synergistically with other cytokines and growth factors on some cell types. Like other growth factors, TNF- α has been associated with wound healing. Both TNF- α and IL-1 β have been proposed to induce activation of fibroblasts and keratinocytes leading to the secretion of nerve growth factor (NGF) associated with wound healing. This last function is critical since it has been shown that NGF is capable of directly increasing the synthesis of SP in dorsal root ganglion cells. The need for understanding the role of SP as an activator of cytokine production is of critical importance, especially in inflammation and tissue repair situations. For this studies rodents is often a preferred species. This study seeks to understand the effects of SP as to cytokine synthesis by a variety of rat cell populations. This will shed some light into one aspect of the effect of SP on infiltrating inflammatory cells and its contribution to wound healing. One critical difference in the study of cytokine secretion has been that traditionally the methodology has been to culture the cells of interest and analyze the supernatant for the presence of cytokines. This posses a disadvantage since the secretion cannot be identified with the specific cell producing it. Our study implements the use of a two color flow cytometric immunolabeling technique that allows for the detection of the cytokine production as well as the phenotype of the cell producing the cytokine of interest. This allows for identifying the specific cytokine production contribution of different sub-populations. TNF- α , a potent lymphoid factor that exerts cytotoxic effects on a wide range of tumor cells and certain other target cells, shows synthesis upregulation upon activation by SP on both T-cell and neutrophil/macrophage (PMN/MAC) populations. SP increases the response of IL-6 secreting cells on both populations tested while the overall synthesis of IL-6 was increased in the PMN/MAC population while no significant change was observed in the T-cell population. The effect on SP on IL-2 secretion was similar to that of IL-6. Both T-cell and PMN/MAC populations showed an increase in the percent of cells expressing IL-2 while there was no significant change in the total synthesis of this cytokine. The effect on IL-1 β was more like TNF- α . The percent of both PMN/MAC and T-cells was increased upon exposure to SP. The over all synthesis of IL-1 β was significantly increased in the PMN/MAC population while the T-cell population appeared no to be affected by SP. Experimentation was carried out to determine the effect(s) of SP on the production of IL-1 â , IL-2, IL-6 and TNF-á by T-lymphocytes, macrophages and neutrophils. Our data demonstrates that pathophysiological levels (10 -7 M) of SP induce production of cytokines in all three cell types. Interestingly, the highest percentage (52.01 ± 3.49) of cells-expressing all four cytokines were T-cells. In contrast, macrophages and neutrophils produced the highest absolute cytokine levels. There was a statistically significant increase in the amount of TNF (62%), IL-6 (75%), and IL-1 (50%) produced after SP stimulation. All values are expressed as percentage of the stimulated sample over the media control. Our findings indicate that SP induces an increase in the number of T-cells and granulocyte/macrophage populations producing cytokine as well as an overall increase in the total amount cytokine synthesized. The PMN/MAC population showed a higher level of cytokine synthesized while the T-cell population shows the highest percentage of cells producing cytokine. This is due to the total number of cells involved. For example, in normal rats the percentage of T-cells in whole blood is approximately 25% with a White Blood Cell count (WBC) of 4 x 10 6 per ml. This translates to 1 X10 6 T-cells/ mL. Likewise there are approximately 63% granulocyte/macrophages in rat whole blood. This translates to 2.52 x 10 6 PMN/MAC cells/mL. The percentage of SP treated T-cells expressing TNF- α was 45.99% or approximately 460 x 10 3 cells, while the corresponding percentage of PMN/MAC cells was 25.16% or approximately 634 x 10 3 cells. This demonstrates that even though the population percentage is higher on the T-cell the total amount of cytokine synthesized is larger in the PMN/MAC population. The over all contribution of cytokine secretion is greater in the PMN/MAC than in the T-cell population. This pattern of the percentage of positive cytokine expression is higher on the T-cell population while the total cytokine synthesis is higher in the PMN/MAC population is consistent throughout this study. If we extrapolate the findings of this whole blood study into what happens during wound healing and inflammation, we would expect to see that the contribution of cytokine synthesis to an injury would be even greater since the cells that primarily infiltrate the wound after trauma or inflammation are granulocytes and macrophages. The underlying mechanism(s) for SP activation of leukocytes may contribute significantly to the understanding of the cutaneous inflammatory cascade and involvement of the peripheral nervous system on the immune system. These findings suggest that SP participates in the complex network of mediators that regulate cutaneous inflammation and potentially the rate of wound healing.
- synergistically with other cytokines and growth factors on some cell types. Like other growth factors, TNF-α has been associated with wound healing. Both TNF-α and IL-1 β have been proposed to induce activation of fibroblasts and keratinocytes leading to the secretion of nerve growth factor (NGF) associated with wound healing. This last function is critical since it has been shown that NGF is capable of directly increasing the synthesis of SP in dorsal root ganglion cells. The need for understanding the role of SP as an activator of cytokine production is of critical importance, especially in inflammation and tissue repair situations. For this studies rodents is often a preferred species. This study seeks to understand the effects of SP as to cytokine synthesis by a variety of rat cell populations. This will shed some light into one aspect of the effect of SP on infiltrating inflammatory cells and its contribution to wound healing. One critical difference in the study of cytokine secretion has been that traditionally the methodology has been to culture the cells of interest and analyze the supernatant for the presence of cytokines. This posses a disadvantage since the secretion cannot be identified with the specific cell producing it. Our study implements the use of a two color flow cytometric immunolabeling technique that allows for the detection of the cytokine production as well as the phenotype of the cell producing the cytokine of interest. This allows for identifying the specific cytokine production contribution of different sub-populations. TNF-α , a potent lymphoid factor that exerts cytotoxic effects on a wide range of tumor cells and certain other target cells, shows synthesis upregulation upon activation by SP on both T-cell and neutrophil/macrophage (PMN/MAC) populations. SP increases the response of IL-6 secreting cells on both populations tested while the overall synthesis of IL-6 was increased in the PMN/MAC population while no significant change was observed in the T-cell population. The effect on SP on IL-2 secretion was similar to that of IL-6. Both T-cell and PMN/MAC populations showed an increase in the percent of cells expressing IL-2 while there was no significant change in the total synthesis of this cytokine. The effect on IL-1 β was more like TNF-α . The percent of both PMN/MAC and T-cells was increased upon exposure to SP. The over all synthesis of IL-1 β was significantly increased in the PMN/MAC population while the T-cell population appeared no to be affected by SP. Experimentation was carried out to determine the effect(s) of SP on the production of IL-1 â , IL-2, IL-6 and TNF-á by T-lymphocytes, macrophages and neutrophils. Our data demonstrates that pathophysiological levels (10 -7 M) of SP induce production of cytokines in all three cell types. Interestingly, the highest percentage (52.01 ± 3.49) of cells-expressing all four cytokines were T-cells. In contrast, macrophages and neutrophils produced the highest absolute cytokine levels. There was a statistically significant increase in the amount of TNF (62%), IL-6 (75%), and IL-1 (50%) produced after SP stimulation. All values are expressed as percentage of the stimulated sample over the media control. Our findings indicate that SP induces an increase in the number of T-cells and granulocyte/macrophage populations producing cytokine as well as an overall increase in the total amount cytokine synthesized. The PMN/MAC population showed a higher level of cytokine synthesized while the T-cell population shows the highest percentage of cells producing cytokine. This is due to the total number of cells involved. For example, in normal rats the percentage of T-cells in whole blood is approximately 25% with a White Blood Cell count (WBC) of 4 x 10 6 per ml. This translates to 1 X10 6 T-cells/ mL. Likewise there are approximately 63% granulocyte/macrophages in rat whole blood. This translates to 2.52 x 10 6 PMN/MAC cells/mL. The percentage of SP treated T-cells expressing TNF- α was 45.99% or approximately 460 x 10 3 cells, while the corresponding percentage of PMN/MAC cells was 25.16% or approximately 634 x 10 3 cells. This demonstrates that even though the population percentage is higher on the T-cell the total amount of cytokine synthesized is larger in the PMN/MAC population. The over all contribution of cytokine secretion is greater in the PMN/MAC than in the T-cell population. This pattern of the percentage of positive cytokine expression is higher on the T-cell population while the total cytokine synthesis is higher in the PMN/MAC population is consistent throughout this study. If we extrapolate the findings of this whole blood study into what happens during wound healing and inflammation, we would expect to see that the contribution of cytokine synthesis to an injury would be even greater since the cells that primarily infiltrate the wound after trauma or inflammation are granulocytes and macrophages. The underlying mechanism(s) for SP activation of leukocytes may contribute significantly to the understanding of the cutaneous inflammatory cascade and involvement of the peripheral nervous system on the immune system. These findings suggest that SP participates in the complex network of mediators that regulate cutaneous inflammation and potentially the rate of wound healing. Functions of activated macrophages. Macrophages may be activated by signals from many surface receptors. The two examples shown are the receptor for bacterial endotoxin (LPS), which transduces signals via an attached Toll-like receptor, and the receptor for the most important macrophage-activating cytokine, IFN-. Signals from activating receptors stimulate the production of several proteins, which mediate the important functions of macrophages. Different macrophage surface receptors may stimulate distinct or overlapping responses. The biochemical signaling pathways used by these receptors are complex; their common feature is that they stimulate the production of transcription factors, which result in the production of various proteins
- synergistically with other cytokines and growth factors on some cell types. Like other growth factors, TNF- α has been associated with wound healing. Both TNF- α and IL-1 β have been proposed to induce activation of fibroblasts and keratinocytes leading to the secretion of nerve growth factor (NGF) associated with wound healing. This last function is critical since it has been shown that NGF is capable of directly increasing the synthesis of SP in dorsal root ganglion cells. The need for understanding the role of SP as an activator of cytokine production is of critical importance, especially in inflammation and tissue repair situations. For this studies rodents is often a preferred species. This study seeks to understand the effects of SP as to cytokine synthesis by a variety of rat cell populations. This will shed some light into one aspect of the effect of SP on infiltrating inflammatory cells and its contribution to wound healing. One critical difference in the study of cytokine secretion has been that traditionally the methodology has been to culture the cells of interest and analyze the supernatant for the presence of cytokines. This posses a disadvantage since the secretion cannot be identified with the specific cell producing it. Our study implements the use of a two color flow cytometric immunolabeling technique that allows for the detection of the cytokine production as well as the phenotype of the cell producing the cytokine of interest. This allows for identifying the specific cytokine production contribution of different sub-populations. TNF- α , a potent lymphoid factor that exerts cytotoxic effects on a wide range of tumor cells and certain other target cells, shows synthesis upregulation upon activation by SP on both T-cell and neutrophil/macrophage (PMN/MAC) populations. SP increases the response of IL-6 secreting cells on both populations tested while the overall synthesis of IL-6 was increased in the PMN/MAC population while no significant change was observed in the T-cell population. The effect on SP on IL-2 secretion was similar to that of IL-6. Both T-cell and PMN/MAC populations showed an increase in the percent of cells expressing IL-2 while there was no significant change in the total synthesis of this cytokine. The effect on IL-1 β was more like TNF- α . The percent of both PMN/MAC and T-cells was increased upon exposure to SP. The over all synthesis of IL-1 β was significantly increased in the PMN/MAC population while the T-cell population appeared no to be affected by SP. Experimentation was carried out to determine the effect(s) of SP on the production of IL-1 â , IL-2, IL-6 and TNF-á by T-lymphocytes, macrophages and neutrophils. Our data demonstrates that pathophysiological levels (10 -7 M) of SP induce production of cytokines in all three cell types. Interestingly, the highest percentage (52.01 ± 3.49) of cells-expressing all four cytokines were T-cells. In contrast, macrophages and neutrophils produced the highest absolute cytokine levels. There was a statistically significant increase in the amount of TNF (62%), IL-6 (75%), and IL-1 (50%) produced after SP stimulation. All values are expressed as percentage of the stimulated sample over the media control. Our findings indicate that SP induces an increase in the number of T-cells and granulocyte/macrophage populations producing cytokine as well as an overall increase in the total amount cytokine synthesized. The PMN/MAC population showed a higher level of cytokine synthesized while the T-cell population shows the highest percentage of cells producing cytokine. This is due to the total number of cells involved. For example, in normal rats the percentage of T-cells in whole blood is approximately 25% with a White Blood Cell count (WBC) of 4 x 10 6 per ml. This translates to 1 X10 6 T-cells/ mL. Likewise there are approximately 63% granulocyte/macrophages in rat whole blood. This translates to 2.52 x 10 6 PMN/MAC cells/mL. The percentage of SP treated T-cells expressing TNF- α was 45.99% or approximately 460 x 10 3 cells, while the corresponding percentage of PMN/MAC cells was 25.16% or approximately 634 x 10 3 cells. This demonstrates that even though the population percentage is higher on the T-cell the total amount of cytokine synthesized is larger in the PMN/MAC population. The over all contribution of cytokine secretion is greater in the PMN/MAC than in the T-cell population. This pattern of the percentage of positive cytokine expression is higher on the T-cell population while the total cytokine synthesis is higher in the PMN/MAC population is consistent throughout this study. If we extrapolate the findings of this whole blood study into what happens during wound healing and inflammation, we would expect to see that the contribution of cytokine synthesis to an injury would be even greater since the cells that primarily infiltrate the wound after trauma or inflammation are granulocytes and macrophages. The underlying mechanism(s) for SP activation of leukocytes may contribute significantly to the understanding of the cutaneous inflammatory cascade and involvement of the peripheral nervous system on the immune system. These findings suggest that SP participates in the complex network of mediators that regulate cutaneous inflammation and potentially the rate of wound healing.
- Oxygen Radicals There are many types of radicals, but those of most concern in biological systems are derived from oxygen, and known collectively as reactive oxygen species . Oxygen has two unpaired electrons in seperate orbitals in its outer shell. This electronic structure makes oxygen especially susceptible to radical formation. Sequential reduction of molecular oxygen (equivalent to sequential addition of electrons) leads to formation of a group of reactive oxygen species: superoxide anion peroxide (hydrogen peroxide) hydroxyl radical The structure of these radicals is shown in the figure below, along with the notation used to denote them. Note the difference between hydroxyl radical and hydroxyl ion, which is not a radical. Another radical derived from oxygen is singlet oxygen , designated as 1O2. This is an excited form of oxygen in which one of the electrons jumps to a superior orbital following absorption of energy. Formation of Reactive Oxygen Species Oxygen-derived radicals are generated constantly as part of normal aerobic life. They are formed in mitochondria as oxygen is reduced along the electron transport chain. Reactive oxygen species are also formed as necessary intermediates in a variety of enzyme reactions. Examples of situations in which oxygen radicals are overproduced in cells include: White blood cells such as neutrophils specialize in producing oxygen radicals, which are used in host defense to kill invading pathogens. Cells exposed to abnormal environments such as hypoxia or hyperoxia generate abundant and often damaging reactive oxygen species. A number of drugs have oxidizing effects on cells and lead to production of oxygen radicals. Ionizing radiation is well known to genereate oxygen radicals within biological systems. Interestingly, the damaging effects of radiation are higher in well oxygenated tissues than in tissues deficient in oxygen.
- Epitope : A part of an antigen to which an antibody binds. Also called the antigenic determinant
- It was so named because it reacts with the somatic C polysaccharide of Streptococcus pneumoniae , and was first discovered in 1930 by Tillet and Frances
- Review Regulation of complement activation by C-reactive protein Carolyn Mold a , , Henry Gewurz c and Terry W. Du Clos b , d a Department of Molecular Genetics and Microbiology, University of New Mexico, Albuquerque, NM 87131, USA b Department of Medicine, University of New Mexico, Albuquerque, NM 87131, USA c Department of Immunology/Microbiology, Rush Medical College, Chicago, IL 60612, USA d Department of Veterans Affairs Medical Center, Albuquerque, NM 87108, USA Accepted 23 December 1998. Available online 17 June 1999. Abstract C-reactive protein (CRP) is an acute-phase serum protein and a mediator of innate immunity. CRP binds to microbial polysaccharides and to ligands exposed on damaged cells. Binding of CRP to these substrates activates the classical complement pathway leading to their uptake by phagocytic cells. Complement activation by CRP is restricted to C1, C4, C2 and C3 with little consumption of C5-9. Surface bound CRP reduces deposition of and generation of C5b-9 by the alternative pathway and deposition of C3b and lysis by the lectin pathway. These activities of CRP are the result of recruitment of factor H resulting in regulation of C3b on bacteria or erythrocytes. Evidence is presented for direct binding of H to CRP. H binding to CRP or C3b immobilized on microtiter wells was demonstrated by ELISA. Attachment of CRP to a surface was required for H binding. H binding to CRP was not inhibited by EDTA or phosphocholine, which inhibit ligand binding, but was inhibited by a 13 amino acid CRP peptide. The peptide sequence was identical to the region of CRP that showed the best alignment to H binding peptides from Streptococcus pyogenes (M6) and Neisseria gonorrhoeae (Por1A). The results suggest that CRP bound to a surface provides secondary binding sites for H resulting in greater regulation of alternative pathway amplification and C5 convertases. Complement activation by CRP may help limit the inflammatory response by providing opsonization with minimal generation of C5a and C5b-9. Author Keywords: Complement; Inflammation; Acute phase reactants; Inflammatory mediators Abbreviations: CRP, C-reactive protein; PC, phosphocholine; MBL, mannan-binding lectin; MASP-1 and -2, MBL-associated serine proteases 1 and 2; ELISA, enzyme-linked immunosorbent assay; IL-6, interleukin 6; IL-1, interleukin 1; PC-BSA, PC-conjugated bovine serum albumin Corresponding author. Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA. Tel.: +1-505-272-5768; fax: +1-505-272-6029 Immunopharmacology Volume 42, Issues 1-3 , May 1999, Pages 23-30
- One of these proteins is chemotactic for monocytes , suggesting that its release may be a way in which neutrophils, also the first cells to reach a site of inflammation, help to attract the "second wave" of leukocytes, i.e., mononuclear phagocytes
- Fig.2-5 The sequence of events in the migration of blood leukocytes to sites of infection. At sites of infection, macrophages that have encountered microbes produce cytokines (e.g., TNF and IL-1) that activate the endothelial cells of nearby venules to produce selectins, ligands for integrins, and chemokines. Selectins mediate weak tethering and rolling of blood neutrophils on the endothelium; integrins mediate firm adhesion of neutrophils; and chemokines activate the neutrophils and stimulate their migration through the endothelium to the site of infection. Blood monocytes and activated T lymphocytes use the same mechanisms to migrate to sites of infection.
- As opposed to Ig Abs which are synthesized in B (plasma) cells only
- The reason why IgG4, IgA & IgE do not activate complement is: They lack C1q receptors; they cannot bind C1q
- Some people asked for this slide Steps of CP activation Step 1: Activation of C1 C1q -FcIgG activates C1r &C1s C1s activates C4 C4a + C4b Step 2: Activation of C4 C4 C4a + C4b Step 3: Activation of C2 by C4b C4b + C2 C4b2a (C3-convertase) + 2b Step 4: Activation of C3 by C3-convertase C3 C3a + C3b END OF THE CP; Next are steps in the common pathway leading to MAC formation Formation of C5-convertase by binding of C3b to C3-convertase: C4b2a + C3b C4b2a3b (C5-convertase) Step 5: Activation of C5, C6 & C7 Step 6: Activation of C8 & C9 MAC: C5b678(C9)6
- Angioedema, Hereditary Article Last Updated: May 18, 2007 AUTHOR AND EDITOR INFORMATION Section 1 of 9 Authors and Editors Introduction Clinical Differentials Workup Treatment Medication Follow-up References Author: Warren R Heymann, MD , Head, Division of Dermatology, Professor, Department of Internal Medicine, University of Medicine and Dentistry of New Jersey Warren R Heymann is a member of the following medical societies: American Academy of Dermatology , American Society of Dermatopathology , and Society for Investigative Dermatology Coauthor(s): Kathleen M Rossy, MD , Staff Physician, Department of Dermatology, New York Medical College, Metropolitan Hospital Editors: Robert A Schwartz, MD, MPH , Professor and Head of Dermatology, Professor of Medicine, Professor of Pediatrics, Professor of Pathology, Professor of Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School; Michael J Wells, MD , Associate Professor, Department of Dermatology, Texas Tech University Health Sciences Center; Paul Krusinski, MD , Director of Dermatology, Professor, Department of Internal Medicine, Fletcher Allen Health Care, University of Vermont; Catherine Quirk, MD , Clinical Assistant Professor, Department of Dermatology, Brown University; William D James, MD , Paul R Gross Professor of Dermatology, University of Pennsylvania School of Medicine; Vice-Chair, Program Director, Department of Dermatology, University of Pennsylvania Health System Author and Editor Disclosure Synonyms and related keywords: hereditary angioedema, HAE, C1-INH, C1 inhibitor, swelling of the skin INTRODUCTION Section 2 of 9 Authors and Editors Introduction Clinical Differentials Workup Treatment Medication Follow-up References Background Hereditary angioedema (HAE) is an autosomal dominant disorder of C1 inhibitor (C1-INH) deficiency manifested by painless, nonpruritic, nonpitting swelling of the skin. Type I HAE is defined by low plasma levels of a normal C1-INH protein. Type II HAE is characterized by the presence of normal or elevated levels of a dysfunctional C1-INH. Type III HAE has been recently identified as an estrogen-dependent inherited form of angioedema occurring mainly in women with normal functional and quantitative levels of C1-INH. Pathophysiology The gene for C1-INH ( SERPING1 ) has been mapped to 11q12-q13.1. C1-INH is a multifunctional serine protease inhibitor that is normally present in high concentrations in plasma. It is the only known plasma inhibitor of C1r and C1s, the activated proteases of the first component of complement. It is also the major plasma inhibitor of activated factor XII (Hageman factor), the first protease in the contact system. Additionally, C1-INH is one of the major inhibitors of plasma kallikrein, the contact system protease that cleaves kininogen and releases bradykinin. Presumably, uncontrolled activation of the contact system allows for the release of kininlike mediators, resulting in edema of subcutaneous or submucosal tissues. Although the issue of which vasoactive peptide is ultimately responsible for these changes remains controversial, direct evidence supports the importance of bradykinin in the clinical manifestations of angioedema. Other kinins may also be pathogenic. The inciting factor responsible for inducing the release of these vasoactive peptides is unclear. Factor XII activation may be secondary to a genetic mutation or phospholipid release from damaged or apoptotic cells and may be important in the generation of bradykinin from endothelial activation. This hypothesis encompasses the role of illness or tissue injury in the generation of bradykinin. HAE is due to mutations within the C1-INH gene ( C1NH ) and is transmitted as an autosomal dominant trait. Approximately 150 different genetic mutations have been described in HAE, and a spontaneous mutation rate of 25% has been reported. The 2 variants of HAE related to C1-INH function are type I (85%) and type II (15%). Type I HAE is characterized by low antigenic and functional plasma levels of a normal C1-INH protein. Type II HAE is characterized by the presence of normal or elevated antigenic levels of a dysfunctional mutant protein together with reduced levels of the functional protein. C1-INH deficiency allows autoactivation of C1, with consumption of C4 and C2. In type III HAE, the C1-INH protein is both qualitatively and functionally normal. The exact mechanism of action responsible for the link between estrogen and angioedema is unclear. One theory suggests that estrogen plays a role in up-regulating the production of bradykinin and decreasing its degradation by angiotensin-converting enzyme (ACE). A more recent theory suggests a mutation in factor XII that allows for the inappropriate activation of the kinin cascade. Frequency International HAE is estimated to occur in 1 in 50,000-150,000 individuals. Mortality/Morbidity Mortality rates are estimated at 15-33%, resulting from laryngeal edema and asphyxiation. Race Persons of any race can be affected, with no reported bias in different ethnic groups. Sex Men and women are equally affected for HAE types I and II. HAE type III was initially thought to occur only in women, but recent family studies have described males with HAE and normal C1 inhibitor levels. Although a few male cases have been cited in the literature, HAE type III is still thought to predominantly affect women. Age C1-INH deficiency is present at birth, although only a few patients have been reported with perinatal angioedema. Symptoms usually become apparent in the first or second decade of life. Approximately 40% of people with HAE experience their first episode before age 5 years, and 75% present before age 15 years. Patients typically experience minor swelling in childhood that may go unnoticed, with increased severity around puberty. HAE is a lifelong affliction, although some report decreased symptoms with age. Five percent of adults with HAE are asymptomatic while carrying the C1NH mutation, and they are only identified after their children are found to be symptomatic. CLINICAL Section 3 of 9 Authors and Editors Introduction Clinical Differentials
- Caused by an autoantibody to C1 inhibitor , or by Monoclonal B-cell proliferation The ultimate result of both causes seems to be the consumption of C1 so it becomes deficient