Re: Complements

[Guest guest]

Patty:

Sorry, evidently I missed your original post on this subject. Do you mind reiterating what Complements are all about?

Thanks.

LM

[Guest guest]

Thanks Patty.

I'm going to get tested.

LM

[Guest guest]

I've been tested but it was ten years ago: the test was called

a C1Q binding and I think it was supposed to tell whether the

complement cascade had been activated. . .it had. I don't

think deficiencies were tested, as I had never been ill.

What was tested a couple of years later were the immunoglobulins

and subclasses. Almost all of the women I knew with silicone-filled

implants had a IgG3 below normal. (This subclass has been known

for many years to be necessary for phagocytosis--it is senstive

to particulates) I would think that a few saline-filled implantees

might test this same way.

Bonnie

[Guest guest]

Doctor didn't say anything--tests were my idea--we pretty well knew

the immune system had been activated--I think this was to tell which part of the immune system had been activated; I remember

that's when we did the ANA, the collagen vascular panel, the

immunoglobulins, the lymphocyte panel and the Rheumatoid Factor.

All showed something other than normal and/or antibodies.

The immunoglobulins were tested again 2+ years later (and

there was improvement) and that's when the IgG3 was found low. This was a different doc, I was much more sick, and much more

was found--although. . .some things that had been found previously

were gone.

I think when the immune system is activated, Prednisone is the

drug of choice.

Do you have ongoing or progressive problems of an immune disease?

Do you think something is going on? I guess what I'm trying to say is

that these are not routine tests--they are performed when there is

an indication of something. That's not to say they can't be performed

if you can find a doc who will do it and you can afford it.

Bonnie

[Guest guest]

Oh PS. If you mean can the C1Q go back to normal--yes.

Antibodies can disappear (none is normal) and immunoglobulins

can go back up or down. . . i.e, the system can become dysregulated and then regulate, and it can become activated

and then calm back down to normal.

Bonnie

[Guest guest]

Hi -Marie,

Actually the original post was forwarded by and discussed the prognosis for those with Complement deficiencies. The complement system is part of the immune system, and the article basically stated that those with certain complement deficiencies are more prone to autoimmune disease over time.

It said something like 79% of C3-deficient patients develop some form of collagen-vascular disease. That was scary to me, because I have tested low in C3 twice.

I was just wondering if anyone else has tested low in the complement system, since it has never really been discussed before, but I do have a study which shows that some women with implants end up with a lowered C3 complement. I didn't realize the significance of that until I saw 's post!

Here it is again, in case you are interested:

----- Original Message ----- From: Kathi

Sent: Saturday, September 14, 2002 4:14 PM

Subject: Complement Deficiencies

Complement Deficiencies Last Updated: January 7, 2002 Synonyms and related keywords: C1qrs deficiency; C3 deficiency; C2, C4 deficiency; C5-9 deficiency; terminal membrane attack complex deficiencies; mannan-binding lectin deficiency AUTHOR INFORMATION Section 1 of 11 Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Pictures Bibliography Author: R Krishna Chaganti, MD, Staff Physician, Department of Internal Medicine, Temple University School of Medicine Coauthor(s): Darrilyn Moyer, MD, Associate Program Director, Associate Professor, Department of Internal Medicine, Temple University School of Medicine; Margaret R Donohoe, MD, Consulting Staff, Department of Allergy and Immunology, Albemarle Hospital; A Schwartz, MD, MPH, Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School Editor(s): Lee Kishiyama, MD, Assistant Clinical Professor of Medicine, University of California at San Francisco School of Medicine, Consulting Staff, Allergy and Asthma Associates of Santa Clara Valley Research Center; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; R Marney, Jr, MD, Director, Associate Professor, Department of Internal Medicine, Division of Allergy and Immunology, Vanderbilt University School of Medicine; D Rice, MD, Associate Professor, Departments of Internal Medicine and Pediatrics and Adolescent Medicine, St Louis University; and A Kaliner, MD, Section Chief of Allergy and Immunology, Clinical Professor, Department of Internal Medicine, Washington University School of Medicine INTRODUCTION Section 2 of 11 Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Pictures Bibliography Background: The complement system is part of the innate immune system. The complement system plays an important part in defense against pyogenic organisms, especially gram-negative bacteria. Deficiencies in the complement cascade can lead to overwhelming infection and sepsis. In addition to playing an important role in host defense against infection, the complement system is a mediator in both the pathogenesis and prevention of immune complex diseases, such as systemic lupus erythematosus (SLE). These findings underscore the duality of the complement system. It has a protective effect when functioning in moderation against appropriate pathogens; at the same time, the inflammation promoted by complement activation can result in cellular damage when not kept in check. We are continuing to learn more about the complement system. New studies point to the complex interplay between the complement cascade and adaptive immune response, and complement also is being studied in association with ischemic injury as a target of therapy. Although the complement system is part of the body’s innate, relatively nonspecific defense against pathogens, its role is hardly primitive or easily understood. This article attempts to outline some of the disease states associated with complement deficiencies and their clinical implications. Pathophysiology: The complement cascade consists of 3 separate pathways that converge in a final common pathway. The pathways include the classical pathway (C1qrs, C2, C4), the alternative pathway (C3, factor B, properdin), and the mannan-binding pathway (mannan-binding lectin [MBL]). These 3 pathways converge at the component C3. The terminal complement pathway consists of all proteins activated after C3; the most notable of these is the C5-9 group of proteins known collectively as the membrane attack complex (MAC). The MAC exerts powerful killing activity by creating perforations in cellular membranes. Deficiencies in complement predispose patients to infection via 2 mechanisms: (1) ineffective opsonization and (2) defects in lytic activity (defects in MAC). Specific complement deficiencies also are associated with an increased risk of developing autoimmune disease, such as SLE. There also is an intricate system that regulates complement activity. The important components of this system are various cell membrane-associated proteins such as complement receptor 1 (CR1), complement receptor 2 (CR2), and decay accelerating factor (DAF). In addition to these cell surface-associated proteins, other plasma proteins regulate specific steps of the classical or alternative pathway; for example, the proteins factor H and factor I inhibit the formation of the enzyme C3 convertase of the alternative pathway. Similarly, the enzyme C1q esterase acts as an inhibitor of the classical pathway serine proteases C1r and C1s. Deficiency of any of these regulatory proteins results in a state of overactivation of the complement system with damaging inflammatory effects. Two clinical manifestations of such deficiencies are paroxysmal nocturnal hemoglobinuria and hereditary angioedema, both of which are discussed in other eMedicine articles. Frequency: Internationally: Complement deficiencies are relatively rare worldwide, and estimates of prevalence are based on screening high-risk populations. Retrospective studies of people with frequent meningococcal infections report varying prevalence based on geographic location. In populations with recurrent meningococcal infection, the prevalence is as high as 30%. Individuals with C1q deficiency have a 93% chance of developing SLE. Similarly, C1rs deficiency has a 57% association with SLE, and C4 deficiency has a 75% association with SLE. Mortality/Morbidity: Individuals with complement deficiencies that hinder opsonization present with frequent recurrent infections and a high rate of morbidity and mortality. Patients with a defect in formation of the MAC have a lesser degree of morbidity and mortality than, for example, patients with a defect in C3; it is thought that the deficiency in the lytic component of the complement cascade may have some protective effect against the generation of full-blown sepsis. Despite this theory, the severity of infection in the MAC-deficient patients should not be underestimated, as they can still be potentially life-threatening. Race: While no definitive racial patterns of association have been established for the majority of complement deficiencies, ethnic predispositions for certain of the complement deficiencies have been described. For example, deficiencies in properdin and C2 have been associated with the Caucasian race; C6 deficiencies have been shown to have a possible predisposition in African populations, and deficiencies in C8 have been associated with an Asian racial background. However, in most of these deficiencies, the absolute number of patients studied has been quite small. Sex: Most complement deficiencies affect both sexes equally. The majority of complement deficiencies are inherited in an autosomal recessive pattern (although MBL deficiency has been described as having both an autosomal dominant and recessive pattern). An exception to the autosomal pattern of inheritance is properdin deficiency, which is an X-linked trait. Age: Individuals with complement deficiencies that hinder opsonization often present at an early age (months to a few years old) because of increased susceptibility to overwhelming infection. Patients with deficiencies in formation of the MAC tend to be slightly older (late teenage years) in presentation. Complement deficiencies associated with immune complex diseases, such as SLE, do not show a clear pattern of age at first presentation. CLINICAL Section 3 of 11 Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Pictures Bibliography History: Infants may have Leiner disease, which manifests in recurrent diarrhea, wasting, and generalized seborrheic dermatitis. The defect in Leiner disease is usually attributed to a defect of the fifth component of complement (C5). However, a child was described by Sonea and associates who had Leiner disease associated with diminished C3, and another was described by Goodyear and Harper with a low level of the fourth component of complement and reduced neutrophil mobility Thus, the C5 defect may not be the sole cause of Leiner disease, as has been suggested; diminished C3 or C4, or C5 dysfunction or deficiency with hypogammaglobulinemia or other lymphoid deficiency is also required for its expression. This section discusses 3 of the major sequelae of complement deficiencies based on the pathophysiology of each defect: defects that result in inadequate opsonization, defects in cell lysis, and the association of complement deficiencies with immune complex diseases. Defects that result in inadequate opsonization Opsonization is the process of coating a pathogenic organism so that it is more easily ingested by the macrophage system. The complement protein C3b, along with its cleavage product C3bi, is a potent agent of opsonization in the complement cascade. Any defect that causes decreased production of C3b results in inadequate opsonization ability. Such opsonization defects can be caused by deficiencies in components of the classical, alternative, or MBL pathways, or defects may be caused by deficiencies of the C3b component itself. The clinical history of patients with classical pathway deficiencies varies slightly from other complement-deficient patients. In the small number of patients studied, patients with classical pathway deficiencies—deficiency of C1qrs, C2, or C4--are similar in presentation to patients with primary immunoglobulin deficiencies. For example, patients tend to have frequent sinopulmonary infections with organisms such as Streptococcus pneumoniae. In order to generate an antibody response, an antigen must bind to the complement receptor (CR2) on B cells and the complement protein C3d. A deficiency of C1-4 proteins leads to an inadequate humoral response in these patients. Patients also have a decrease in classical pathway production of the opsonin C3b, but it seems that the alternative and MBL pathways compensate for this defect since opsonin is not completely absent. Opsonization defects also can be caused by alternative pathway deficiencies. In the alternative pathway, a deficiency of factor B, factor D, or properdin can result in a decreased amount of C3b. Deficiencies in properdin have been described in some detail. Properdin is a protein encoded on the X chromosome. Properdin stabilizes the C3 convertase (C3bBb) of the alternative pathway. Stabilization of C3 convertase increases the half-life of the complex from 5 minutes to 30 minutes, exponentially increasing the amount of C3b that can be deposited on a microbial surface. The role of C3b as an opsonin is essential in defense against neisserial infection, and the risk of overwhelming neisserial infection increases in the absence of properdin. The third pathway whose deficiencies can result in opsonization defects is the MBL pathway. MBL is one of the collectin proteins. These proteins share specific structural characteristics, namely the presence of a collagenlike region and a Ca2+-dependent lectin domain. Of all of the lectin proteins, only MBL has been shown to have the ability to activate the complement system. The MBL protein can activate the C4 and C2 components of complement by forming a complex with serine proteases known as MASP1 and MASP2. MASP1 and MASP2 activation results in the protein products C3 and C3b. The MBL protein is versatile because it can bind to a variety of substrates, prompting some to describe the MBL as a kind of universal antibody. Clinically, MBL deficiencies increase risk of infection with the yeast Saccharomyces cerevisiae and encapsulated bacteria such as Neisseria meningitidis and S pneumoniae. Finally, absolute deficiencies of C3 itself also result in defective opsonization. The C3 component occupies an important place at the junction of both the classical and alternative pathways. As such, C3 deficiency results in severe opsonization dysfunction. C3 deficiency also causes deficient leukocyte chemotaxis because of decreased C3a concentrations and decreased bactericidal killing secondary to decreased formation of MAC. Clinically, patients present at an early age with overwhelming infections from encapsulated bacteria. In addition to opsonization problems, C3 deficiency also impairs adequate clearance of circulating immune complexes, and 79% of C3-deficient patients develop some form of collagen-vascular disease. Deficiencies of the inhibitory proteins of the classical and alternative pathways also can result in a functional C3 deficiency through uncontrolled consumption of C3. Factor H and factor I are proteins that inhibit C3 formation in the alternative and classical pathways, respectively. Deficiencies in either of these C3 inhibitors can result in an overactivation of C3 and subsequent C3 depletion. Clinically, patients are similar to other absolute C3-deficient patients described above. Defects in cell lysis Complement deficiencies of the terminal cascade proteins also predispose patients to infection, but the clinical history of these patients is different. The terminal complement proteins are the proteins in the cascade that form the MAC—complement proteins C5-9. These proteins are responsible for bactericidal killing of organisms such as N meningitidis. The frequency of meningococcal infection in terminal complement-deficient patients is as high as 66%. In addition to this high rate of first-time infection, frequency of recurrence with the same organism also is as high as 50%. The serogroups of N meningitidis responsible for infections in this group tend to be the more rare serogroups Y and W135, rather than the more common serogroups B, A, and C. Clinically, terminal-deficient patients tend to present with infection at a later age than patients with other complement deficiencies. These terminal-deficient individuals also have less morbidity and mortality associated with infection. Unlike classical pathway-deficient patients, humoral immunity is intact, but lysis of pathogenic organisms is impaired. While recurrent infection with Neisseria species has been the predominant clinical finding in patients with complement deficiencies, the complement system is important in defending against other pathogens as well. Both the opsonization and lytic function of complement protect against a variety of other nonbacterial pathogens, such fungi, viruses, and mycobacteria. The role of complement in defense against viral infection is sufficiently important that pathogenic viruses have had to develop strategies to evade complement activation. For example, human immunodeficiency virus 1 (HIV-1) recently has been described as escaping complement-mediated lysis through the incorporation of regulatory proteins, such as DAF, into the viral envelope. Similarly, other viruses also have evolved complement-specific means of escape. Complement deficiencies and associated immune complex diseases Patients with complement deficiencies of the classical pathway are predisposed to develop immune complex diseases. History in these patients is similar to that of other patients who meet the criteria for immune complex diseases, such as SLE; however, the pathophysiology behind the association of complement deficiency and the pathogenesis of diseases such as SLE is only beginning to be understood. Complement itself is the source of several stimulators of an inflammatory response through generation of anaphylatoxin byproducts and the final MAC. It would seem that complement deficiencies should decrease the amount of inflammation responsible for the pathology found in autoimmune diseases; however, early classical pathway complement deficiencies have been associated with an increased frequency of autoimmune diseases, such as SLE. Patients with deficiencies of the classical pathway components C1qrs, C2, or C4 have been shown to have an increased likelihood of developing SLE. Homozygous deficiency of C1q has the highest association with SLE, with a recently quoted prevalence of 93%. Subsequent components of the classical pathway have a respective prevalence of 57% for C1rs deficiency, 75% association with homozygous C4 deficiencies, and 10% prevalence in patients with C2 deficiencies. Why does complement deficiency increase the risk of developing SLE? Complement helps in the prevention of immune complex disease by decreasing the number of circulating immune complexes; the greater the concentration of these precipitating immune complexes, the higher the likelihood that they will deposit in nearby tissues and cause an inflammatory response. Complement aids in neutralization and clearance of antigen-antibody complexes in several ways. The classical pathway acts to inhibit immune complex precipitation by physically interfering with immune complex aggregation. Secondly, complement enhances the clearance of circulating immune complexes by binding to complement receptors (CR1) on cells such as erythrocytes, B lymphocytes, T lymphocytes, and macrophages. When complement (specifically C3b) binds to CR1 on erythrocytes, the immune complex can be transported through the circulation to be presented to the macrophage systems in the spleen and liver. Lastly, the classical pathway also can recognize and clear apoptotic cells, which decreases the possibility that these cells can act as autoantigens. Physical: There are no specific physical findings that are pathognomonic for complement deficiencies. Rather, clinical manifestations are representative of the infections and immune complex diseases to which patients are prone. Since N meningitidis is the overwhelmingly prevalent bacterial pathogen in these patients, knowledge of the physical characteristics of disseminated meningococcal disease is important. The characteristic maculopapular rash that occurs in up to 75% of individuals with meningococcemia occurs soon after disease onset. The rash consists of pink lesions on the trunk and extremities; lesions are approximately 2-10 mm in diameter. As described elsewhere, the rash can quickly progress to hemorrhagic lesions. Petechiae also are a prominent finding and can occur on the skin of the trunk and extremities or on mucous membranes, such as the palate and conjunctivae. Noninfectious diseases, such as SLE, that are associated with complement deficiencies also can have a characteristic physical presentation. Complement deficiencies associated with the deposition of immune complexes in various tissues can result in many of the sequelae of SLE, such as glomerulonephritis, arthralgia, uveitis, and vasculitic rash. Causes: Most complement deficiencies are caused by a genetic defect in one of the genes that codes for the various complement proteins. No clear environmental or drug-related causes have been identified. DIFFERENTIALS Section 4 of 11 Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Pictures Bibliography Hypocomplementemia Hypogammaglobulinemia Immunoglobulin A Deficiency Immunoglobulin D Deficiency Immunoglobulin G Deficiency Immunoglobulin M Deficiency Immunosuppression Meningococcal Infections Meningococcemia Sepsis, Bacterial Septic Shock Systemic Lupus Erythematosus Urticaria Other Problems to be Considered: Hypocomplementemic urticarial vasculitis syndrome (HUVS) childhood seborrheic dermatitis childhood erythroderma & n bsp; Related Articles Hypocomplementemia Hypogammaglobulinemia ImmunoglobulinA Deficiency ImmunoglobulinD Deficiency ImmunoglobulinG Deficiency ImmunoglobulinM Deficiency Immunosuppression Meningococcal Infections Meningococcemia Sepsis,Bacterial Septic Shock Systemic Lupus Erythematosus Urticaria WORKUP Section 5 of 11 Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Pictures Bibliography Lab Studies: Deficiencies in complement can be screened for by using the CH50 test or AP50 test. The CH50 specifically tests for deficiencies in the classical pathway by measuring the ability of the patient’s serum to lyse antibody-coated sheep erythrocytes. A deficiency in any of the classical proteins results in a CH50 of zero. Similarly, the AP50 tests for alternative pathway activity. Direct measurement of individual serum complement proteins, such as C3 and C4, also can be done and is helpful in determining the diagnosis. Imaging Studies: No specific imaging studies are indicated. Consider a head CT prior to lumbar puncture in a patient with suspected meningitis. Other Tests: As mentioned in the outpatient management section, patients with classical complement pathway deficiencies should be screened for sequelae of immune-complex diseases. Urinalysis and complete blood count should be performed on these patients. Procedures: In a patient with suspected meningitis, a lumbar puncture should be performed to assist in the definitive diagnosis of bacterial meningitis. TREATMENT Section 6 of 11 Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Pictures Bibliography Medical Care: Definitive treatment of complement deficiencies would require replacement of the missing component of the cascade, either through direct infusion of the protein or through gene therapy. Since neither of these options is currently available, treatment of these patients is focused on managing the sequelae of the particular complement deficiencies. For many patients, treatment will need to be focused on eradicating a particular infection, especially with encapsulated organisms such as N meningitidis. In most cases of meningococcal disease, treatment with meningeal doses of a third-generation cephalosporin covers most strains of N meningitidis. For other patients, the complement deficiency may manifest as episodic flares of autoimmune diseases; treatment of these patients should focus on immunosuppressive therapy of these diseases. It is important to note, however, that some overlap often exists between an increased susceptibility to infection and the greater tendency to develop autoimmune disease; both of these clinical situations may need to be addressed simultaneously in any one patient. Consultations: In a patient with a suspected complement deficiency, consider an allergy and immunology consult to determine appropriate diagnostic tests. Also, consider rheumatology or infectious disease consult to manage acute complications of the complement deficiency. Diet: There are no specific diet restrictions. Activity: Activity can continue as tolerated. MEDICATION Section 7 of 11 Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Pictures Bibliography Cephalosporins often are used for treatment of N meningitidis infection in complement-deficient patients. Third-generation or fourth-generation cephalosporins are used for coverage of infection with any of the encapsulated bacteria. Drug Category: Antibiotics -- Therapy must cover all likely pathogens in the context of this clinical setting. Antibiotic selection should be guided by blood culture sensitivity whenever feasible. Drug Name Ceftriaxone (Rocephin) -- Third-generation cephalosporin with broad-spectrum, gram-negative activity; lower efficacy against gram-positive organisms; higher efficacy against resistant organisms. Arrests bacterial growth by binding to one or more penicillin-binding proteins. Adult Dose Meningitis: 2 g IV qd Pediatric Dose Not established Contraindications Documented hypersensitivity Interactions Probenecid may increase ceftriaxone levels; coadministration with ethacrynic acid, furosemide, and aminoglycosides may increase nephrotoxicity Pregnancy B - Usually safe but benefits must outweigh the risks. Precautions Adjust dose in renal impairment; caution in breastfeeding women and allergy to penicillin Drug Name Cefepime (Maxipime) -- Fourth-generation cephalosporin with good gram-negative coverage. Similar to third-generation cephalosporins, but has better gram-positive coverage. Adult Dose 1-2 g IV q12h for 5-10 d; may administer higher or more frequent dosages depending on severity of infection Pediatric Dose Not established Contraindications Documented hypersensitivity Interactions Probenecid may increase effects; aminoglycosides increase nephrotoxic potential of cefepime Pregnancy B - Usually safe but benefits must outweigh the risks. Precautions Adjust dose in severe renal insufficiency (high doses may cause CNS toxicity); prolonged use of cefepime may predispose patients to superinfection FOLLOW-UP Section 8 of 11 Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Pictures Bibliography Further Inpatient Care: Serious infectious states warrant hospitalization for treatment. Inpatient stay is not necessarily needed to screen for complement deficiencies if the patient is asymptomatic. Further Outpatient Care: Patients with a known complement deficiency should be screened for glomerular or immune complex disease. Obtain a urinalysis to check for proteinuria and rheumatologic serologies to screen for SLE. In/Out Patient Meds: Cephalosporins (third or fourth generation) are needed for treatment of meningeal infection. Deterrence/Prevention: Administration of the multivalent meningococcal vaccine in patients with known complement deficiency is recommended, especially those patients deficient in the MAC proteins. Similarly, administration of the pneumococcal vaccine and the Haemophilus Influenzae vaccine also may provide protection against these encapsulated organisms. Complications: Complications of complement deficiencies can be serious; severe CNS damage and death from meningitis are among the worst possible adverse outcomes. Prognosis: In general, the prognosis for patients with C3 deficiencies is poorer than that of other complement-deficient individuals. Patients may have severe, recurrent episodes of meningococcal infection from as early as a few months of age. Many can succumb to sepsis early in life. Patients with deficiencies in the MAC, while still highly susceptible to infection, can have a slightly less severe course than C3-deficient patients. They too can present with neisserial infections, but the infection is not always as overwhelming in its course. Patient Education: Patients with an identified complement deficiency should be counseled regarding possible complications and risks associated with this deficiency. Family members should be screened for complement deficiencies and counseled regarding possible risks. MISCELLANEOUS Section 9 of 11 Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Pictures Bibliography Medical/Legal Pitfalls: Missed diagnosis BIBLIOGRAPHY Section 11 of 11 Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Pictures Bibliography Beynon HL, Davies KA, Haskard DO: Erythrocyte complement receptor type 1 and interactions between immune complexes, neutrophils, and endothelium. J Immunol 1994 Oct 1; 153(7): 3160-7[Medline]. Brandtzaeg P, Mollnes TE, Kierulf P: Complement activation and endotoxin levels in systemic meningococcal disease. J Infect Dis 1989 Jul; 160(1): 58-65[Medline]. Carroll MC: The role of complement in B cell activation and tolerance. Adv Immunol 2000; 74: 61-88[Medline]. Davies KA, s AM, Beynon HL: Immune complex processing in patients with systemic lupus erythematosus. In vivo imaging and clearance studies. J Clin Invest 1992 Nov; 90(5): 2075-83[Medline]. Davies KA, Erlendsson K, Beynon HL: Splenic uptake of immune complexes in man is complement-dependent. J Immunol 1993 Oct 1; 151(7): 3866-73[Medline]. Dempsey PW, ME, Akkaraju S: C3d of complement as a molecular adjuvant: bridging innate and acquired immunity. Science 1996 Jan 19; 271(5247): 348-50[Medline]. Densen P, Weiler JM, Griffiss JM: Familial properdin deficiency and fatal meningococcemia. Correction of the bactericidal defect by vaccination. N Engl J Med 1987 Apr 9; 316(15): 922-6[Medline]. Doody GM, Dempsey PW, Fearon DT: Activation of B lymphocytes: integrating signals from CD19, CD22 and Fc gamma RIIb1. Curr Opin Immunol 1996 Jun; 8(3): 378-82[Medline]. Fauci A, Braunwald E, Isselbacher KJ: Meningococcal Infections. In: on's Principles of Internal Medicine 1998; 910-915. Figueroa JE, Densen P: Infectious diseases associated with complement deficiencies. Clin Microbiol Rev 1991 Jul; 4(3): 359-95[Medline]. MM: Complement deficiencies. Pediatr Clin North Am 2000 Dec; 47(6): 1339-54[Medline]. Girardin E, Grau GE, Dayer JM: Tumor necrosis factor and interleukin-1 in the serum of children with severe infectious purpura. N Engl J Med 1988 Aug 18; 319(7): 397-400[Medline]. Goodnow CC: Pathways for self-tolerance and the treatment of autoimmune diseases. Lancet 2001 Jun 30; 357(9274): 2115-21[Medline]. Goodyear HM, Harper JI: Leiner's disease associated with metabolic acidosis. Clin Exp Dermatol 1989 Sep; 14(5): 364-6[Medline]. Kuby J: The Complement System. Immunology 1997; 335-355. Lehner PJ, Davies KA, Walport MJ: Meningococcal septicaemia in a C6-deficient patient and effects of plasma transfusion on lipopolysaccharide release. Lancet 1992 Dec 5; 340(8832): 1379-81[Medline]. Leitao MF, Vilela MM, Rutz R: Complement factor I deficiency in a family with recurrent infections. Immunopharmacology 1997 Dec; 38(1-2): 207-13[Medline]. Lutz HU: How pre-existing, germline-derived antibodies and complement may help induce a primary immune response to nonself. Scand J Immunol 1999 Mar; 49(3): 224-8[Medline]. Medof ME, Iida K, Mold C: Unique role of the complement receptor CR1 in the degradation of C3b associated with immune complexes. J Exp Med 1982 Dec 1; 156(6): 1739-54[Medline]. Pickering MC, Botto M, PR: Systemic lupus erythematosus, complement deficiency, and apoptosis. Adv Immunol 2000; 76: 227-324[Medline]. Prodinger WM: Complement receptor type two (CR2,CR21): a target for influencing the humoral immune response and antigen-trapping. Immunol Res 1999; 20(3): 187-94[Medline]. Ross GD, Yount WJ, Walport MJ: Disease-associated loss of erythrocyte complement receptors (CR1, C3b receptors) in patients with systemic lupus erythematosus and other diseases involving autoantibodies and/or complement activation. J Immunol 1985 Sep; 135(3): 2005-14[Medline]. Rother K, Till GO, Hansch GM: The Complement System. 1997. Schlesinger M, Nave Z, Levy Y: Prevalence of hereditary properdin, C7 and C8 deficiencies in patients with meningococcal infections. Clin Exp Immunol 1990 Sep; 81(3): 423-7[Medline]. Soderstrom C, Braconier JH, sson D: Bactericidal activity for Neisseria meningitidis in properdin-deficient sera. J Infect Dis 1987 Jul; 156(1): 107-12[Medline]. Sonea MJ, Moroz BE, Reece ER: Leiner's disease associated with diminished third component of complement. Pediatr Dermatol 1987 Aug; 4(2): 105-7[Medline]. Sullivan, KE, Winkelstein, JA: Genetically Determined Deficiencies of the Complement System. Primary Immunodeficiency Diseases, edited by Ochs, HD, Edvard , CI, Puck, J 1999; 397-416. Sumiya M, Super M, Tabona P: Molecular basis of opsonic defect in immunodeficient children. Lancet 1991 Jun 29; 337(8757): 1569-70[Medline]. Summerfield JA, Sumiya M, Levin M: Association of mutations in mannose binding protein gene with childhood infection in consecutive hospital series. BMJ 1997 Apr 26; 314(7089): 1229-32[Medline]. Super M, Thiel S, Lu J: Association of low levels of mannan-binding protein with a common defect of opsonisation. Lancet 1989 Nov 25; 2(8674): 1236-9[Medline]. Tolnay M, Tsokos GC: Complement receptor 2 in the regulation of the immune response. Clin Immunol Immunopathol 1998 Aug; 88(2): 123-32[Medline]. MW: Mannose-binding lectin: the pluripotent molecule of the innate immune system. Immunol Today 1996 Nov; 17(11): 532-40[Medline]. Volanakis JE, MM: The Human Complement System in Health and Disease. 1998. Walport MJ: Complement. First of two parts. N Engl J Med 2001 Apr 5; 344(14): 1058-66[Medline]. Walport MJ: Complement. Second of two parts. N Engl J Med 2001 Apr 12; 344(15): 1140-4[Medline]. Walport MJ, Lachmann PJ: Erythrocyte complement receptor type 1, immune complexes, and the rheumatic diseases. Arthritis Rheum 1988 Feb; 31(2): 153-8[Medline]. Walport MJ, Davies KA, Botto M: C1q and systemic lupus erythematosus. Immunobiology 1998 Aug; 199(2): 265-85[Medline]. Wisnieski JJ, Baer AN, Christensen J: Hypocomplementemic urticarial vasculitis syndrome. Clinical and serologic findings in 18 patients. Medicine (Baltimore) 1995 Jan; 74(1): 24-41[Medline]. ----- Original Message -----

From: perlesetlacet@...

Sent: Tuesday, September 17, 2002 4:23 PM

Subject: Re: Complements

Patty:Sorry, evidently I missed your original post on this subject. Do you mind reiterating what Complements are all about?Thanks.LM

[Guest guest]

Bonnie,

When the test results showed that the complement cascade had been activated, what did your doctor say about it? Did he offer anything in the way of a remedy? I am just wondering if this can go back to normal once abnormal....anyone know?

Patty

----- Original Message -----

From: Bos@...

Sent: Tuesday, September 17, 2002 5:44 PM

Subject: Re: Complements

I've been tested but it was ten years ago: the test was called a C1Q binding and I think it was supposed to tell whether the complement cascade had been activated. . .it had. I don't think deficiencies were tested, as I had never been ill. What was tested a couple of years later were the immunoglobulins and subclasses. Almost all of the women I knew with silicone-filled implants had a IgG3 below normal. (This subclass has been known for many years to be necessary for phagocytosis--it is senstive to particulates) I would think that a few saline-filled implantees might test this same way. Bonnie

[Guest guest]

Patty, Complement can be affected by things as simple as allergies. There are also various tests used to check the complement cascade, and depending on which one the doc orders, they can come up false positive or false negative, as some are much more sensitive (and specific) than others. In addition, in my personal experience working alongside and with infectious disease docs, most pts demonstrate some sort of clinical signs/symptoms of autoimmune illness (fatigue, ulcerated skin indicative of SLE, candidiasis, rashes, burning, dry eyes, peripheral vascular insufficiency, LOC (level of consciousness) changes, pain, fever, enlarged lymph nodes, organomegaly (enlarged organs, such as liver and spleen), decreased ROM, and adventitious breath sounds, among others, including neurological changes. However, I've seen pts come in to be worked up for some sort of illness, and it turns out they have simple allergies, yet those allergies activated the complement cascade. The results of your test(s) will need to correlate with any signs/symptoms you're having, and then your doc needs to decide if further tests need to be done. There are so many tests and when you start doing these tests, they are very expensive (my protein electrophoresis and immunoelectrophoresis combined cost me over $500). The docs I've worked with, and in my own personal experience from being worked up for all sorts of autoimmune illnesses, is that docs will only order tests if you've got signs/symtoms that are indicative of something going on, and they need more specific and sensitive tests. But the cascade complement can be turned on and off depending on what's going on with your body, so yes, it is possible that these lab results can change. Hence the importance of getting a redraw before drawing any conclusions. e ----- Original Message ----- From: Bos@... Sent: Tuesday, September 17, 2002 6:54 PM Subject: Re: Complements Doctor didn't say anything--tests were my idea--we pretty well knew the immune system had been activated--I think this was to tell which part of the immune system had been activated; I remember that's when we did the ANA, the collagen vascular panel, the immunoglobulins, the lymphocyte panel and the Rheumatoid Factor. All showed something other than normal and/or antibodies. The immunoglobulins were tested again 2+ years later (and there was improvement) and that's when the IgG3 was found low. This was a different doc, I was much more sick, and much more was found--although. . .some things that had been found previously were gone. I think when the immune system is activated, Prednisone is the drug of choice. Do you have ongoing or progressive problems of an immune disease? Do you think something is going on? I guess what I'm trying to say is that these are not routine tests--they are performed when there is an indication of something. That's not to say they can't be performed if you can find a doc who will do it and you can afford it. Bonnie

[Guest guest]

Thanks e,

That makes me feel alot better! Maybe it is allergies, as I have experienced more allergic reactions to foods since implants. Before implants, I had no allergies at all.

Patty

----- Original Message -----

From: e Rene

Sent: Tuesday, September 17, 2002 9:49 PM

Subject: Re: Complements

Patty,

Complement can be affected by things as simple as allergies. There are also various tests used to check the complement cascade, and depending on which one the doc orders, they can come up false positive or false negative, as some are much more sensitive (and specific) than others. In addition, in my personal experience working alongside and with infectious disease docs, most pts demonstrate some sort of clinical signs/symptoms of autoimmune illness (fatigue, ulcerated skin indicative of SLE, candidiasis, rashes, burning, dry eyes, peripheral vascular insufficiency, LOC (level of consciousness) changes, pain, fever, enlarged lymph nodes, organomegaly (enlarged organs, such as liver and spleen), decreased ROM, and adventitious breath sounds, among others, including neurological changes. However, I've seen pts come in to be worked up for some sort of illness, and it turns out they have simple allergies, yet those allergi es activated the complement cascade. The results of your test(s) will need to correlate with any signs/symptoms you're having, and then your doc needs to decide if further tests need to be done.

There are so many tests and when you start doing these tests, they are very expensive (my protein electrophoresis and immunoelectrophoresis combined cost me over $500). The docs I've worked with, and in my own personal experience from being worked up for all sorts of autoimmune illnesses, is that docs will only order tests if you've got signs/symtoms that are indicative of something going on, and they need more specific and sensitive tests. But the cascade complement can be turned on and off depending on what's going on with your body, so yes, it is possible that these lab results can change. Hence the importance of getting a redraw before drawing any conclusions.

e

----- Original Message -----

From: Bos@...

Sent: Tuesday, September 17, 2002 6:54 PM

Subject: Re: Complements

Doctor didn't say anything--tests were my idea--we pretty well knew the immune system had been activated--I think this was to tell which part of the immune system had been activated; I remember that's when we did the ANA, the collagen vascular panel, the immunoglobulins, the lymphocyte panel and the Rheumatoid Factor. All showed something other than normal and/or antibodies. The immunoglobulins were tested again 2+ years later (and there was improvement) and that's when the IgG3 was found low. This was a different doc, I was much more sick, and much more was found--although. . .some things that had been found previously were gone. I think when the immune system is activated, Prednisone is the drug of choice. Do you have ongoing or progressive problems of an immune disease? Do you think something is going on? I guess what I'm trying to say is that these are not routine tests--they are performed when there is an indication of something. That's not to say they can't be performed if you can find a doc who will do it and you can afford it. Bonnie

[Guest guest]

Patty

the other thing about these tests is that different labs have different measurements. In CA for example an ANA is positive about .40 in Idaho it is .80 not that it is a big difference but it can make a difference if the amount is small. Also like my rheumy told me once, ana can be affected by medications, supplements, inflammation, etc etc, so really if you have only had these tested 2x I would say you don't have enough to really truly be worried about yet. I would def get worked up again. Just insist that you want to be worked up for autoimmune disease. It is good to be informed and to know what is going on. Then you also have a baseline to go by as far as where you are at right now.

I bet you will find that your labs are probably normal or moving towards normal again.

For me I new when my ANA was high, I swear I could feel that it was high, sure enough that time in CA my ANA was sky high at 1.640 and I remember when I was finally feeling better and just had a feeling it had come down, that was in Idaho and it was normal. It has continued to be normal ever since.

Not that you can always tell but I swear I new when mine was high cause I could feel the inflammation going on.

I had a rheumy tell me that the numbers didn't mean much cause they often go up and down in autoimmune disease but I disagree because in my case I don't think it was true autoimmune disease but just an autoimmune reaction brought on by silicone toxicity.

anyhow get them rechecked you will have more peace of mind then. I have always found that knowledge is power. It will be worth the $$ to know what your dealing with too.

Hugs

C

----- Original Message -----

From: ~*Patty*~

Sent: Wednesday, September 18, 2002 7:29 AM

Subject: Re: Complements

Thanks e,

That makes me feel alot better! Maybe it is allergies, as I have experienced more allergic reactions to foods since implants. Before implants, I had no allergies at all.

Patty

----- Original Message -----

From: e Rene

Sent: Tuesday, September 17, 2002 9:49 PM

Subject: Re: Complements

Patty,

Complement can be affected by things as simple as allergies. There are also various tests used to check the complement cascade, and depending on which one the doc orders, they can come up false positive or false negative, as some are much more sensitive (and specific) than others. In addition, in my personal experience working alongside and with infectious disease docs, most pts demonstrate some sort of clinical signs/symptoms of autoimmune illness (fatigue, ulcerated skin indicative of SLE, candidiasis, rashes, burning, dry eyes, peripheral vascular insufficiency, LOC (level of consciousness) changes, pain, fever, enlarged lymph nodes, organomegaly (enlarged organs, such as liver and spleen), decreased ROM, and adventitious breath sounds, among others, including neurological changes. However, I've seen pts come in to be worked up for some sort of illness, and it turns out they have simple allergies, yet those allergi es activated the complement cascade. The results of your test(s) will need to correlate with any signs/symptoms you're having, and then your doc needs to decide if further tests need to be done.

There are so many tests and when you start doing these tests, they are very expensive (my protein electrophoresis and immunoelectrophoresis combined cost me over $500). The docs I've worked with, and in my own personal experience from being worked up for all sorts of autoimmune illnesses, is that docs will only order tests if you've got signs/symtoms that are indicative of something going on, and they need more specific and sensitive tests. But the cascade complement can be turned on and off depending on what's going on with your body, so yes, it is possible that these lab results can change. Hence the importance of getting a redraw before drawing any conclusions.

e

----- Original Message -----

From: Bos@...

Sent: Tuesday, September 17, 2002 6:54 PM

Subject: Re: Complements

Doctor didn't say anything--tests were my idea--we pretty well knew the immune system had been activated--I think this was to tell which part of the immune system had been activated; I remember that's when we did the ANA, the collagen vascular panel, the immunoglobulins, the lymphocyte panel and the Rheumatoid Factor. All showed something other than normal and/or antibodies. The immunoglobulins were tested again 2+ years later (and there was improvement) and that's when the IgG3 was found low. This was a different doc, I was much more sick, and much more was found--although. . .some things that had been found previously were gone. I think when the immune system is activated, Prednisone is the drug of choice. Do you have ongoing or progressive problems of an immune disease? Do you think something is going on? I guess what I'm trying to say is that these are not routine tests--they are performed when there is an indication of something. That's not to say they can't be performed if you can find a doc who will do it and you can afford it. Bonnie

[Guest guest]

Hopefully this will be the case, , and they will be normal again. I am expecting it, as I have been feeling really, really good. Even have my period with no real brain fog at all. I think the thyroid medication is helping me very much. I have not had a bad bout of brain fog in quite awhile, and no feeling of tiredness.

I'll let you know what happens. I have to go get more blood drawn as the lab either lost my specimen, spilled it, whatever, and this was for all the testing on my parathyroid and thyroid--much more detailed testing. I just want to know if I am dealing with an autoimmune thyroid condition for sure.

Anyway, I am staying positive about all this, and I am not going to get all whacked out about the lowered complement. I feel good, and I am treasuring it! I have lost 13 pounds, I feel better about myself, and I am pretty sure that it will continue.

Patty

----- Original Message -----

From: Heer

Sent: Wednesday, September 18, 2002 6:39 AM

Subject: Re: Complements

Patty

the other thing about these tests is that different labs have different measurements. In CA for example an ANA is positive about .40 in Idaho it is .80 not that it is a big difference but it can make a difference if the amount is small. Also like my rheumy told me once, ana can be affected by medications, supplements, inflammation, etc etc, so really if you have only had these tested 2x I would say you don't have enough to really truly be worried about yet. I would def get worked up again. Just insist that you want to be worked up for autoimmune disease. It is good to be informed and to know what is going on. Then you also have a baseline to go by as far as where you are at right now.

I bet you will find that your labs are probably normal or moving towards normal again.

For me I new when my ANA was high, I swear I could feel that it was high, sure enough that time in CA my ANA was sky high at 1.640 and I remember when I was finally feeling better and just had a feeling it had come down, that was in Idaho and it was normal. It has continued to be normal ever since.

Not that you can always tell but I swear I new when mine was high cause I could feel the inflammation going on.

I had a rheumy tell me that the numbers didn't mean much cause they often go up and down in autoimmune disease but I disagree because in my case I don't think it was true autoimmune disease but just an autoimmune reaction brought on by silicone toxicity.

anyhow get them rechecked you will have more peace of mind then. I have always found that knowledge is power. It will be worth the $$ to know what your dealing with too.

Hugs

C

----- Original Message -----

From: ~*Patty*~

Sent: Wednesday, September 18, 2002 7:29 AM

Subject: Re: Complements

Thanks e,

That makes me feel alot better! Maybe it is allergies, as I have experienced more allergic reactions to foods since implants. Before implants, I had no allergies at all.

Patty

----- Original Message -----

From: e Rene

Sent: Tuesday, September 17, 2002 9:49 PM

Subject: Re: Complements

Patty,

Complement can be affected by things as simple as allergies. There are also various tests used to check the complement cascade, and depending on which one the doc orders, they can come up false positive or false negative, as some are much more sensitive (and specific) than others. In addition, in my personal experience working alongside and with infectious disease docs, most pts demonstrate some sort of clinical signs/symptoms of autoimmune illness (fatigue, ulcerated skin indicative of SLE, candidiasis, rashes, burning, dry eyes, peripheral vascular insufficiency, LOC (level of consciousness) changes, pain, fever, enlarged lymph nodes, organomegaly (enlarged organs, such as liver and spleen), decreased ROM, and adventitious breath sounds, among others, including neurological changes. However, I've seen pts come in to be worked up for some sort of illness, and it turns out they have simple allergies, yet those allergi es activated the complement cascade. The results of your test(s) will need to correlate with any signs/symptoms you're having, and then your doc needs to decide if further tests need to be done.

There are so many tests and when you start doing these tests, they are very expensive (my protein electrophoresis and immunoelectrophoresis combined cost me over $500). The docs I've worked with, and in my own personal experience from being worked up for all sorts of autoimmune illnesses, is that docs will only order tests if you've got signs/symtoms that are indicative of something going on, and they need more specific and sensitive tests. But the cascade complement can be turned on and off depending on what's going on with your body, so yes, it is possible that these lab results can change. Hence the importance of getting a redraw before drawing any conclusions.

e

----- Original Message -----

From: Bos@...

Sent: Tuesday, September 17, 2002 6:54 PM

Subject: Re: Complements

Doctor didn't say anything--tests were my idea--we pretty well knew the immune system had been activated--I think this was to tell which part of the immune system had been activated; I remember that's when we did the ANA, the collagen vascular panel, the immunoglobulins, the lymphocyte panel and the Rheumatoid Factor. All showed something other than normal and/or antibodies. The immunoglobulins were tested again 2+ years later (and there was improvement) and that's when the IgG3 was found low. This was a different doc, I was much more sick, and much more was found--although. . .some things that had been found previously were gone. I think when the immune system is activated, Prednisone is the drug of choice. Do you have ongoing or progressive problems of an immune disease? Do you think something is going on? I guess what I'm trying to say is that these are not routine tests--they are performed when there is an indication of something. That's not to say they can't be performed if you can find a doc who will do it and you can afford it. Bonnie

[Guest guest]

Patty--

All sounds reasonable to me!

You that that saying, "If it's not broken. . ."

I took Prednisone for seven months in my "medically naive years." I don't know if I would take it again or not--don't know what the alternative is and probably should

investigate it as it seems to be the aspirin of the day.

Glad the Cytomel is working for you!

Bonnie

[Guest guest]

Bonnie,

I tested positive for rheumatoid factor and lowered C3 complement(first time back in 1998 when I got the implants out, was sick and the explanting doc told me to see a rheumy), but no diagnosis of any autoimmune disease. That was good actually for me and my insurance! I've skated on that since 1998, because I basically gave up on docs and went the alternative route. I had my rheumatoid factor and C3 tested again in Feb. 2001 because I had two bladder infections (or mild kidney infections, not sure, but it sure did hurt in my back area), and those were the tests the doc ordered when he asked about my history. He did nothing. Most recently I had an alternative doc tell me he thought I had an autoimmune thyroid problem based on some blood work. I don't think anything is going on now that wasn't going on before. Maybe just now they are actually figuring out the thyroid problem. Anyway, I feel way, way better than I have at any time since I got sick from implants, probably from the Cytomel I am taking.

I would never, ever, ever and I mean NEVER take prednisone. Too many nasty side effects. I've heard it makes women feel really good when they are having an autoimmune flare, but no way for me.

Anyway, I am not worried about it anymore. I will have the C3 checked again eventually, but I am not going to run out and panic about it--I did at first because that article said some scary things about a lowered C3 complement, but I feel good now, and that is all that counts.

Thanks Bonnie,

Patty

----- Original Message -----

From: Bos@...

Sent: Tuesday, September 17, 2002 6:54 PM

Subject: Re: Complements

Doctor didn't say anything--tests were my idea--we pretty well knew the immune system had been activated--I think this was to tell which part of the immune system had been activated; I remember that's when we did the ANA, the collagen vascular panel, the immunoglobulins, the lymphocyte panel and the Rheumatoid Factor. All showed something other than normal and/or antibodies. The immunoglobulins were tested again 2+ years later (and there was improvement) and that's when the IgG3 was found low. This was a different doc, I was much more sick, and much more was found--although. . .some things that had been found previously were gone. I think when the immune system is activated, Prednisone is the drug of choice. Do you have ongoing or progressive problems of an immune disease? Do you think something is going on? I guess what I'm trying to say is that these are not routine tests--they are performed when there is an indication of something. That's not to say they can't be performed if you can find a doc who will do it and you can afford it. Bonnie

[Guest guest]

Hi Ladies,

I guess I'm extremely 'lucky', as my Internist has only given me very limited amounts of any form of steroids, and only for very severe situations, "to break the pain cycle"....... followed by the statement, "this turns your bones to 'dust', at any age"!

MM

Martha Murdock, DirectorNational Silicone Implant Foundation | Dallas Headquarters"Supporting Survivors of Medical Implant Devices"4416 Willow LaneDallas, TX 75244-7537

----- Original Message -----

From: Bos@...

Sent: Wednesday, September 18, 2002 7:43 PM

Subject: Re: Complements

Patty-- All sounds reasonable to me! You that that saying, "If it's not broken. . ." I took Prednisone for seven months in my "medically naive years." I don't know if I would take it again or not--don't know what the alternative is and probably should investigate it as it seems to be the aspirin of the day. Glad the Cytomel is working for you! Bonnie