DOCSLIB.ORG

Uva-DARE (Digital Academic Repository)

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Uva-DARE (Digital Academic Repository) UvA-DARE (Digital Academic Repository) Flow cytometric immunophenotyping in the diagnosis and follow-up of immunodeficient children de Vries, E.; Noordzij, J.G.; Kuijpers, T.W.; van Dongen, J.J.M. DOI 10.1007/s004310100797 Publication date 2001 Published in European Journal of Pediatrics Link to publication Citation for published version (APA): de Vries, E., Noordzij, J. G., Kuijpers, T. W., & van Dongen, J. J. M. (2001). Flow cytometric immunophenotyping in the diagnosis and follow-up of immunodeficient children. European Journal of Pediatrics, 160(10), 583-591. https://doi.org/10.1007/s004310100797 General rights It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons). Disclaimer/Complaints regulations If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: https://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. UvA-DARE is a service provided by the library of the University of Amsterdam (https://dare.uva.nl) Download date:25 Sep 2021 Eur J Pediatr -2001) 160: 583±591 DOI 10.1007/s004310100797 REVIEW Esther de Vries á Jeroen G. Noordzij á Taco W. Kuijpers Jacques J.M. van Dongen Flow cytometric immunophenotyping in the diagnosis and follow-up of immunode®cient children Received: 29 March 2001 / Accepted: 15 May 2001 / Published online: 19 July 2001 Ó Springer-Verlag 2001 Abstract From time to time, paediatricians are con- immunode®cient children according to the four main fronted with children who might suer from a primary clinical categories. immunode®ciency disease. For practical purposes, these children can be divided into four main clinical catego- Keywords Flow cytometry á Immunode®ciency á ries: -1) a relatively large group of childrenwith recur- Immunophenotyping rent ear-nose and throat and lower respiratory tract infections, in some cases caused by de®ciencies of anti- Abbreviations AID activation-induced cytidine bodies or complement; -2) children with failure to thrive, deaminase á BTK Bruton tyrosine kinase á intractable diarrhoea or an opportunistic infection CD40L CD40 ligand á ENT ear-nose and throat á which canbe caused by a T-lymphocyte or combined FSC forward scatter á HIV humanimmunode®ciency immunode®ciency; -3) children with infections with py- virus á IFN interferon á IL interleukin á LWB lysed ogenic bacteria or fungi as seen in case of granulocyte/ whole blood á McAb monoclonal antibody á monocyte function de®ciency; and -4) a small hetero- SCID severe combined immunode®ciency á SSC side geneous group of children with recurrence of particular scatter á TCR T-cell receptor á ICF immunode®ciency- infections. Also, acquired immunode®ciency becomes a centromeric instability-facial dysmorphism more commonproblem inpaediatric practice. Flow cy- tometric immunophenotyping of leucocytes appears to be an ecient and rapid tool in the diagnosis and follow- Introduction up of immunode®cient patients, supporting early rec- ognition, before serious infections have compromised From time to time, paediatricians are confronted with the child's general condition. This technique can now be childrenwho might suer from a primary immuno- performed inmanyhospitals. Inthis review, we give de®ciency disease [21]. For practical purposes, these directions for the use of ¯ow cytometric immunophe- children can be divided into four main clinical catego- notyping of leucocytes in the diagnosis and follow-up of ries [7, 26, 28]. The ®rst clinical category comprises the relatively large group of childrenwith recurrent ear-nose and throat -ENT) and lower respiratory tract infections, only in some cases caused by an underlying E. de Vries -&) á J.G. Noordzij á J.J.M. vanDongen immunode®ciency, especially if encapsulated extracel- Department of Immunology, Erasmus University Rotterdam, lular bacteria are found as pathogens. In patients with PO Box 1738, Rotterdam, The Netherlands, hypo- or agammaglobulinaemia, de®cient opsonisation Tel.: +31-10-4088094 with antibodies leads to impaired phagocytosis of these Fax: +31-10-4089456 micro-organisms. Complement de®ciencies are rare and E. de Vries inmost types of complementde®ciencyaected chil- Department of Paediatrics, Bosch Medicentrum, dren present with collagen-vascular disease [15]. How- `s-Hertogenbosch, The Netherlands ever, some complement de®ciencies lead to severely T.W. Kuijpers impaired opsonisation with recurrent serious bacterial Department of Paediatrics, Academic Medical Centre, Amsterdam, The Netherlands infections resembling agammaglobulinaemia -C3 de®- ciency, factor D de®ciency and factor I de®ciency; to a T.W. Kuijpers Department of Experimental Immunohaematology, lesser extent C2 de®ciency). Most children with recur- Central Laboratory of the Netherlands Red Cross Blood rent, often viral, ENT and lower respiratory tract Transfusion Service, Amsterdam, The Netherlands infections do not have an antibody or complement 584 de®ciency, but are immunocompetent. Their problems of their light scatter characteristics, such as forward are due to other more commoncauses such as bron- scatter -FSC) as measure for size, and side scatter -SSC) chial hyperreactivity, adenoidal hypertrophy, or an as measure for cellular irregularity -Fig. 1) [12]. Leuco- allergic constitution, or they may suer from rare cyte count and dierential cell count can then be used to non-immunological diseases like cystic ®brosis or calculate absolute counts of the blood lymphocyte sub- immotile cilia syndrome. populations, which should be compared with age- The second clinical category comprises children with matched reference values [6]. failure to thrive, intractable diarrhoea or an opportu- Blood sample handling, cell separation methodology nistic infection, which can be caused by a T-lymphocyte and labelling techniques in¯uence the reliability of the or combined immunode®ciency with absent or func- results obtained by ¯ow cytometric immunopheno- tionally de®cient T-lymphocytes. Their defence against typing of leucocytes [12]. Dead cells show increased intracellular micro-organisms is inadequate. The third auto¯uorescence, potentially leading to incorrect inter- clinical category comprises children with super®cial and pretation of staining results. This can be minimised by systemic infections with pyogenic bacteria or fungi, who using freshly collected samples which are fully analysed apparently have problems with their ®rst line of within24 h. The immunophenotypingprocedures take defence against invading micro-organisms as in cases 4±5 h, implying that the sample should arrive in the of granulocyte/monocyte function de®ciency. Finally, laboratory in the morning. Cell separation via density the fourth clinical category comprises a small hetero- gradients may result in dierential loss of speci®c lym- geneous group of children with recurrence of particular phocyte subpopulations. This is avoided when the lysed infections such as recurrent neisserial infections in cases whole blood -LWB) technique is used. The currently of late complement component de®ciency, or recurrent available LWB techniques require fewer preparation mycobacterial infections in cases with a defect in the steps and less sample handling via direct incubation of interferon -IFN)-c receptor, interleukin -IL)-12 or the the anticoagulated blood with McAbs, in combination IL-12 receptor [19]. These last three clinical categories with red blood cell lysis. These LWB techniques also are only rarely encountered in general paediatric prac- reduce non-speci®c binding of McAbs, especially if the tice. applied McAbs are directly conjugated with ¯uoro- Most cases of acquired immunode®ciency are iatro- chromes. genic and can therefore be anticipated: as more and more children are being treated with immunosuppressive drugs, aggressive chemotherapy protocols, and stem cell transplantation, acquired immunode®ciency becomes a more commonproblem inpaediatric practice [4]. Also, the prevalence of paediatric human immunode®ciency virus -HIV) infection in Europe is increasing, especially in children born to parents who originate from HIV- endemic areas [8]. Laboratory studies for identi®cation and clinical follow-up of immunode®cient children can now be per- formed inmanyhospitals. Inthis review, we focus our discussion on the increasingly important role of ¯ow cytometric immunophenotyping of leucocytes in the di- agnosis and follow-up of immunocompromised children inpaediatric practice [12]. Applicationof ¯ow cyto- metric techniques helps to speed up the diagnostic pro- cess, thereby supporting early recognition of primary immunode®ciencies before serious infections have com- promised the child's general condition, reducing the Fig. 1 Flow cytometric immunophenotyping of lymphocytes in the chances of survival [21]. blood of a BTK-de®cient X-linked agammaglobulinaemia patient as compared to a healthy control. -A) Analysis of peripheral blood of a healthy control. Dot plot with FSC and SSC showing ``lympho-gate'', ``mono-gate'', and ``granulo-gate'' -left). The Flow cytometric
Load more

Recommended publications
  • Are Complement Deficiencies Really Rare?
    G Model MIMM-4432; No. of Pages 8 ARTICLE IN PRESS Molecular Immunology xxx (2014) xxx–xxx Contents lists available at ScienceDirect Molecular Immunology j ournal homepage: www.elsevier.com/locate/molimm Review Are complement deficiencies really rare? Overview on prevalence, ଝ clinical importance and modern diagnostic approach a,∗ b Anete Sevciovic Grumach , Michael Kirschfink a Faculty of Medicine ABC, Santo Andre, SP, Brazil b Institute of Immunology, University of Heidelberg, Heidelberg, Germany a r a t b i c s t l e i n f o r a c t Article history: Complement deficiencies comprise between 1 and 10% of all primary immunodeficiencies (PIDs) accord- Received 29 May 2014 ing to national and supranational registries. They are still considered rare and even of less clinical Received in revised form 18 June 2014 importance. This not only reflects (as in all PIDs) a great lack of awareness among clinicians and gen- Accepted 23 June 2014 eral practitioners but is also due to the fact that only few centers worldwide provide a comprehensive Available online xxx laboratory complement analysis. To enable early identification, our aim is to present warning signs for complement deficiencies and recommendations for diagnostic approach. The genetic deficiency of any Keywords: early component of the classical pathway (C1q, C1r/s, C2, C4) is often associated with autoimmune dis- Complement deficiencies eases whereas individuals, deficient of properdin or of the terminal pathway components (C5 to C9), are Warning signs Prevalence highly susceptible to meningococcal disease. Deficiency of C1 Inhibitor (hereditary angioedema, HAE) Meningitis results in episodic angioedema, which in a considerable number of patients with identical symptoms Infections also occurs in factor XII mutations.
    [Show full text]
  • Practice Parameter for the Diagnosis and Management of Primary Immunodeficiency
    Practice parameter Practice parameter for the diagnosis and management of primary immunodeficiency Francisco A. Bonilla, MD, PhD, David A. Khan, MD, Zuhair K. Ballas, MD, Javier Chinen, MD, PhD, Michael M. Frank, MD, Joyce T. Hsu, MD, Michael Keller, MD, Lisa J. Kobrynski, MD, Hirsh D. Komarow, MD, Bruce Mazer, MD, Robert P. Nelson, Jr, MD, Jordan S. Orange, MD, PhD, John M. Routes, MD, William T. Shearer, MD, PhD, Ricardo U. Sorensen, MD, James W. Verbsky, MD, PhD, David I. Bernstein, MD, Joann Blessing-Moore, MD, David Lang, MD, Richard A. Nicklas, MD, John Oppenheimer, MD, Jay M. Portnoy, MD, Christopher R. Randolph, MD, Diane Schuller, MD, Sheldon L. Spector, MD, Stephen Tilles, MD, Dana Wallace, MD Chief Editor: Francisco A. Bonilla, MD, PhD Co-Editor: David A. Khan, MD Members of the Joint Task Force on Practice Parameters: David I. Bernstein, MD, Joann Blessing-Moore, MD, David Khan, MD, David Lang, MD, Richard A. Nicklas, MD, John Oppenheimer, MD, Jay M. Portnoy, MD, Christopher R. Randolph, MD, Diane Schuller, MD, Sheldon L. Spector, MD, Stephen Tilles, MD, Dana Wallace, MD Primary Immunodeficiency Workgroup: Chairman: Francisco A. Bonilla, MD, PhD Members: Zuhair K. Ballas, MD, Javier Chinen, MD, PhD, Michael M. Frank, MD, Joyce T. Hsu, MD, Michael Keller, MD, Lisa J. Kobrynski, MD, Hirsh D. Komarow, MD, Bruce Mazer, MD, Robert P. Nelson, Jr, MD, Jordan S. Orange, MD, PhD, John M. Routes, MD, William T. Shearer, MD, PhD, Ricardo U. Sorensen, MD, James W. Verbsky, MD, PhD GlaxoSmithKline, Merck, and Aerocrine; has received payment for lectures from Genentech/ These parameters were developed by the Joint Task Force on Practice Parameters, representing Novartis, GlaxoSmithKline, and Merck; and has received research support from Genentech/ the American Academy of Allergy, Asthma & Immunology; the American College of Novartis and Merck.
    [Show full text]
  • European Society for Immunodeficiencies (ESID)
    Journal of Clinical Immunology https://doi.org/10.1007/s10875-020-00754-1 ORIGINAL ARTICLE European Society for Immunodeficiencies (ESID) and European Reference Network on Rare Primary Immunodeficiency, Autoinflammatory and Autoimmune Diseases (ERN RITA) Complement Guideline: Deficiencies, Diagnosis, and Management Nicholas Brodszki1 & Ashley Frazer-Abel2 & Anete S. Grumach3 & Michael Kirschfink4 & Jiri Litzman5 & Elena Perez6 & Mikko R. J. Seppänen7 & Kathleen E. Sullivan8 & Stephen Jolles9 Received: 5 June 2019 /Accepted: 20 January 2020 # The Author(s) 2020 Abstract This guideline aims to describe the complement system and the functions of the constituent pathways, with particular focus on primary immunodeficiencies (PIDs) and their diagnosis and management. The complement system is a crucial part of the innate immune system, with multiple membrane-bound and soluble components. There are three distinct enzymatic cascade pathways within the complement system, the classical, alternative and lectin pathways, which converge with the cleavage of central C3. Complement deficiencies account for ~5% of PIDs. The clinical consequences of inherited defects in the complement system are protean and include increased susceptibility to infection, autoimmune diseases (e.g., systemic lupus erythematosus), age-related macular degeneration, renal disorders (e.g., atypical hemolytic uremic syndrome) and angioedema. Modern complement analysis allows an in-depth insight into the functional and molecular basis of nearly all complement deficiencies. However, therapeutic options remain relatively limited for the majority of complement deficiencies with the exception of hereditary angioedema and inhibition of an overactivated complement system in regulation defects. Current management strategies for complement disor- ders associated with infection include education, family testing, vaccinations, antibiotics and emergency planning. Keywords Complement .
    [Show full text]
  • Complement Activation in 22Q11.2 Deletion Syndrome
    Journal of Clinical Immunology (2020) 40:515–523 https://doi.org/10.1007/s10875-020-00766-x ORIGINAL ARTICLE Complement Activation in 22q11.2 Deletion Syndrome Dina Grinde1 & Torstein Øverland2 & Kari Lima2,3 & Camilla Schjalm4 & Tom Eirik Mollnes4,5,6 & Tore G. Abrahamsen7,8 Received: 9 July 2019 /Accepted: 19 February 2020 /Published online: 9 March 2020 # The Author(s) 2020 Abstract The 22q11.2 deletion syndrome (22q11.2 del), also known as DiGeorge syndrome, is a genetic disorder with an estimated incidence of 1:3000 to 1:6000 births. These patients may suffer from affection of many organ systems with cardiac malformations, immuno- deficiency, hypoparathyroidism, autoimmunity, palate anomalies, and psychiatric disorders being the most frequent. The importance of the complement system in 22q11.2 del has not been investigated. The objective of this study was to evaluate the complement system in relation to clinical and immunological parameters in patients. A national cohort of patients (n = 69) with a proven heterozygous deletion of chromosome 22q11.2 and a group of age and sex matched controls (n = 56) were studied. Functional capacity of the classical, lectin, and alternative pathways of the complement system as well as complement activation products C3bc and terminal complement complex (TCC) were accessed and correlated to clinical features. All patients in our study had normal complement activation in both classical and alternative pathways. The frequency of mannose-binding lectin deficiency was com- parable to the normal population. The patients had significantly raised plasma levels of C3bc and a slight, but not significant, increase in TCC compared with controls.
    [Show full text]
  • Complement Component 5 Contributes to Poor Disease Outcome in Humans and Mice with Pneumococcal Meningitis
    Complement component 5 contributes to poor disease outcome in humans and mice with pneumococcal meningitis Bianca Woehrl, … , Uwe Koedel, Diederik van de Beek J Clin Invest. 2011;121(10):3943-3953. https://doi.org/10.1172/JCI57522. Research Article Immunology Pneumococcal meningitis is the most common and severe form of bacterial meningitis. Fatality rates are substantial, and long-term sequelae develop in about half of survivors. Disease outcome has been related to the severity of the proinflammatory response in the subarachnoid space. The complement system, which mediates key inflammatory processes, has been implicated as a modulator of pneumococcal meningitis disease severity in animal studies. Additionally, SNPs in genes encoding complement pathway proteins have been linked to susceptibility to pneumococcal infection, although no associations with disease severity or outcome have been established. Here, we have performed a robust prospective nationwide genetic association study in patients with bacterial meningitis and found that a common nonsynonymous complement component 5 (C5) SNP (rs17611) is associated with unfavorable disease outcome. C5 fragment levels in cerebrospinal fluid (CSF) of patients with bacterial meningitis correlated with several clinical indicators of poor prognosis. Consistent with these human data, C5a receptor–deficient mice with pneumococcal meningitis had lower CSF wbc counts and decreased brain damage compared with WT mice. Adjuvant treatment with C5-specific monoclonal antibodies prevented death in all mice with pneumococcal meningitis. Thus, our results suggest C5-specific monoclonal antibodies could be a promising new antiinflammatory adjuvant therapy for pneumococcal meningitis. Find the latest version: https://jci.me/57522/pdf Research article Complement component 5 contributes to poor disease outcome in humans and mice with pneumococcal meningitis Bianca Woehrl,1 Matthijs C.
    [Show full text]
  • Aberrant Complement System Activation in Neurological Disorders
    International Journal of Molecular Sciences Review Aberrant Complement System Activation in Neurological Disorders Karolina Ziabska , Malgorzata Ziemka-Nalecz, Paulina Pawelec, Joanna Sypecka and Teresa Zalewska * Mossakowski Medical Research Centre, NeuroRepair Department, Polish Academy of Sciences, 5 Pawinskiego Street, 02-106 Warsaw, Poland; [email protected] (K.Z.); [email protected] (M.Z.-N.); [email protected] (P.P.); [email protected] (J.S.) * Correspondence: [email protected]; Tel.: +48-(22)-608-65-29; Fax: +48-(22)-608-66-23 Abstract: The complement system is an assembly of proteins that collectively participate in the functions of the healthy and diseased brain. The complement system plays an important role in the maintenance of uninjured (healthy) brain homeostasis, contributing to the clearance of invading pathogens and apoptotic cells, and limiting the inflammatory immune response. However, overacti- vation or underregulation of the entire complement cascade within the brain may lead to neuronal damage and disturbances in brain function. During the last decade, there has been a growing interest in the role that this cascading pathway plays in the neuropathology of a diverse array of brain disorders (e.g., acute neurotraumatic insult, chronic neurodegenerative diseases, and psychiatric disturbances) in which interruption of neuronal homeostasis triggers complement activation. Dys- function of the complement promotes a disease-specific response that may have either beneficial or detrimental effects. Despite recent advances, the explicit link between complement component regulation and brain disorders remains unclear. Therefore, a comprehensible understanding of such relationships at different stages of diseases could provide new insight into potential therapeutic targets to ameliorate or slow progression of currently intractable disorders in the nervous system.
    [Show full text]
  • Primary Immunodeficiencies MEGAN A
    Primary Immunodeficiencies MEGAN A. COOPER, PH.D., The Ohio State University College of Medicine and Public Health, Columbus, Ohio THOMAS L. POMMERING, D.O., Grant Family Practice Residency, Columbus, Ohio KATALIN KORÁNYI, M.D., Children’s Hospital, Columbus, Ohio Primary immunodeficiencies include a variety of disorders that render patients more susceptible to infections. If left untreated, these infections may be fatal. The disorders O A patient informa- constitute a spectrum of more than 80 innate defects in the body’s immune system. Pri- tion handout on the warning signs of mary immunodeficiencies generally are considered to be relatively uncommon. There primary immunodefi- may be as many as 500,000 cases in the United States, of which about 50,000 cases are ciency, adapted with diagnosed each year. Common primary immunodeficiencies include disorders of permission from a list humoral immunity (affecting B-cell differentiation or antibody production), T-cell of warning signs pre- defects and combined B- and T-cell defects, phagocytic disorders, and complement pared by The Jeffrey Modell Foundation, deficiencies. Major indications of these disorders include multiple infections despite is provided on page aggressive treatment, infections with unusual or opportunistic organisms, failure to 2011. thrive or poor growth, and a positive family history. Early recognition and diagnosis can alter the course of primary immunodeficiencies significantly and have a positive effect on patient outcome. (Am Fam Physician 2003;68:2001-8,2011. Copyright 2003© American Academy of Family Physicians.) urrently, more than 80 primary into subgroups based on the component of the immunodeficiencies are rec- immune system that is affected.
    [Show full text]
  • Pan-Cancer Analysis of Immune Complement Signature C3/C5/C3AR1/C5AR1 in Association with Tumor Immune Evasion and Therapy Resistance
    cancers Article Pan-Cancer Analysis of Immune Complement Signature C3/C5/C3AR1/C5AR1 in Association with Tumor Immune Evasion and Therapy Resistance Bashir Lawal 1,2,† , Sung-Hui Tseng 3,4,†, Janet Olayemi Olugbodi 5, Sitthichai Iamsaard 6 , Omotayo B. Ilesanmi 7 , Mohamed H. Mahmoud 8 , Sahar H. Ahmed 9, Gaber El-Saber Batiha 10 and Alexander T. H. Wu 11,12,13,14,15,* 1 PhD Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei 11031, Taiwan; [email protected] 2 Graduate Institute for Cancer Biology & Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan 3 Department of Physical Medicine and Rehabilitation, Taipei Medical University Hospital, Taipei 11031, Taiwan; [email protected] 4 Department of Physical Medicine and Rehabilitation, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan 5 Department of Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA; [email protected] 6 Department of Anatomy, Faculty of Medicine and Research Institute for Human High Performance and Citation: Lawal, B.; Tseng, S.-H.; Health Promotion (HHP&HP), Khon Kaen University, Khon Kaen 40002, Thailand; [email protected] 7 Department of Biochemistry, Faculty of Science, Federal University Otuoke, Olugbodi, J.O.; Iamsaard, S.; Ilesanmi, Ogbia 23401, Bayelsa State, Nigeria; [email protected] O.B.; Mahmoud, M.H.; Ahmed, S.H.; 8 Department
    [Show full text]
  • Complement As a Therapeutic Target in Systemic Autoimmune Diseases
    cells Review Complement as a Therapeutic Target in Systemic Autoimmune Diseases María Galindo-Izquierdo * and José Luis Pablos Alvarez Servicio de Reumatología, Instituto de Investigación 12 de Octubre, Universidad Complutense de Madrid, 28040 Madrid, Spain; [email protected] * Correspondence: [email protected] Abstract: The complement system (CS) includes more than 50 proteins and its main function is to recognize and protect against foreign or damaged molecular components. Other homeostatic functions of CS are the elimination of apoptotic debris, neurological development, and the control of adaptive immune responses. Pathological activation plays prominent roles in the pathogenesis of most autoimmune diseases such as systemic lupus erythematosus, antiphospholipid syndrome, rheumatoid arthritis, dermatomyositis, and ANCA-associated vasculitis. In this review, we will review the main rheumatologic autoimmune processes in which complement plays a pathogenic role and its potential relevance as a therapeutic target. Keywords: complement system; pathogenesis; therapeutic blockade; rheumatic autoimmune diseases 1. Introduction The complement system (CS) includes more than 50 proteins that can be found as soluble forms, anchored to the cell membranes, or intracellularly [1]. Most of the com- plement proteins are synthesized in the liver, although other cell types, especially mono- cytes/macrophages, can produce them. Tissue distribution is variable and a higher con- Citation: Galindo-Izquierdo, M.; centration of these proteins is found in certain locations such as the kidney or brain. The Pablos Alvarez, J.L. Complement as a main function of the CS is to recognize and protect against foreign or damaged molecular Therapeutic Target in Systemic components, directly as microorganisms, and indirectly as immune complexes (IC).
    [Show full text]
  • Complement Factor I Deficiency Associated with Recurrent Meningitis Coinciding with Menstruation
    OBSERVATION Complement Factor I Deficiency Associated With Recurrent Meningitis Coinciding With Menstruation Carolina Gonza´lez-Rubio, PhD; Antonio Ferreira-Cerda´n, MD, PhD; Isabel M. Ponce, BS; Javier Arpa, MD, PhD; Gumersindo Fonta´n, MD, PhD; Margarita Lo´pez-Trascasa, PhD Background: Complement (C) factor I deficiency is a munosorbent assay. This total deficiency was also found rare immunodeficiency state frequently associated with in her sister. Her parents and brother had approxi- recurrent pyogenic infections in early infancy. This de- mately half of the normal levels. In addition, the patient ficiency causes a permanent uncontrolled activation of had very low levels of C3; factor B; and an important re- the alternative pathway resulting in massive consump- duction of factor H, properdin, C5, C7, and C8 comple- tion of C3. ment components. Additional studies in the patient’s sera evidenced high levels of immune complexes containing Patient: A 23-year-old woman with monthly recurrent C1q and immunoglobulin (Ig) G, as well as C3b/factor meningitis episodes, mostly in the perimenstrual period, H, C3b/properdin, C3b/IgG, and properdin/IgG com- since August 1999. Previously, at age 16 years, she had plexes. Treatment with prophylactic antibiotics, anti- meningococcal sepsis, also coinciding with menstruation. estrogen medication, plasma infusions, or intravenous immunoglobulin has been unsuccessful in avoiding con- Objectives: To study the patient and her family to secutive meningitis episodes. elucidate the molecular defects in the pedigree and to evaluate her clinical evolution. Conclusion: For the first time to our knowledge, these data present an unusual relationship between meningi- Results: We describe clinical, immunological, and tis episodes and menstruation in factor I immunodefi- treatment follow-up during this period.
    [Show full text]
  • Chapter 16 Complement Deficiencies
    Complement Deficiencies Chapter 16 Complement Deficiencies Complement is the term used to describe a group of serum proteins that are critically important in our defense against infection. There are deficiencies of each of the individual components of complement. Patients with complement deficiencies encounter clinical problems that depend on the role of the specific complement protein in normal function. Description of the Complement System and Its Pathways The complement system consists of more than 30 system and those of adaptive or acquired immunity. It proteins, present in blood and tissues, as well as other also interacts with proteins of the coagulation and kinin proteins anchored on the surfaces of cells. The primary generating systems along with others. functions of the complement system are to protect from Complement activation is tightly regulated and designed infection, to remove particulate substances, (like to kill invading microbes while producing minimal damaged or dying cells, microbes or immune “collateral damage” that could result in the destruction complexes) and to help modulate adaptive immune of host tissues. Complement proteins in the circulation responses. As part of the innate immune system, are not activated until triggered by an encounter with a complement acts immediately to start the process of bacterial cell, a virus, an immune complex, damaged removal and resolution of the problem. Complement tissue or other substance not usually present in the works with the inflammatory cells of the innate immune body. CHAPTER 16; FIGURE 1 Complement activation is a cascading event like the falling of a row of dominoes. It must follow a specific order if the end result is to be achieved.
    [Show full text]
  • The New Generation of Complement Inhibitors and Implications for Clinical Practice and Vaccination Policy
    The new generation of complement inhibitors and implications for clinical practice and vaccination policy Muhamed-Kheir TAHA MD, PhD London MRF Meeting Institut Pasteur 06/11/2019 Invasive Bacterial Infections Activation of the complement - Humoral innate immunity system - Acute-phase proteins -19 plasma and at least 9 membrane proteins Harris et al., Molecular Immunology 102 (2018) 89–119 Complement pathophysiology AD, Alzheimer’s disease AMD,Age-related macular degeneration DAMP, damage-associated molecular pattern; DDD, dense deposit disease; PAMP, pathogen-associated molecular pattern; PMN, polymorphonuclear cell; PNH, paroxysmal nocturnal hemoglobinuria; SLE, systemic lupus erythematosus. Ricklin &Lambris J Immunol. 2013 Pipeline for anti-complement drugs in the kidney, eye and vasculature Harris et al., Molecular Immunology 102 (2018) 89–119 Half-life of ravulizumab is 4 times longer than that of eculizumab (Lee et al., Blood, 2016) Complement inhibition and hemolysis in PNH Eculizumab Compstatin No Complement Complement Complement Complement activation Activation on PNH RBC Inhibition (C5 inhibition) Inhibition (inhibition on PNH RBC of C3b deposition) on CD55 PNH RBC impact on both pathways (C3b) CD59 (MAC) No lysis Lysis of PNH RBC Lysis of PNH RBC is still occurring - Insertion of C5b-9 MAC Opsonization with C3b (intravascular hemolysis) (extravascular hemolysis) - Opsonization with C3b (extravascular hemolysis) Risk groups for IMD Medical reasons - Close contacts of patients with IMD; - Subjects with a terminal complement deficiency
    [Show full text]