[CIS-PAGID] Complement sequencing

[Sergio Rosenzweig]

Thanks you all for your input and suggestions.

Below are the other tests done on this gentleman:
-HCV serology and PCR: Neg
-Cryoglobulins and cryofibrinogen: Neg
-Immunofixation (multiple times): no paraproteins
-C1Q: normal at 5.8-8.4 (NV 5-8.6); functional 23 units/ml (34-63)
-C1 esterase inh: normal at 19; functional: 90% of normal
-C2: <1.3 multiple times
-C3: always around 40-50
-C4: always <1.5
-CIC: Normal by Raji cells, and by IMMCO, Inc (I don't know the method they use); borderline high by PEG at 3.5mg/dl (NV <3.5) and high by C3D at 15ug/ml (NV 0-8)

I'll keep you posted about his outcome.
Sergio

Sergio D. Rosenzweig, MD, PhD
Chief, Infectious Diseases Susceptibility Unit
Laboratory of Host Defenses, NIAID, NIH
10 Center Dr., Bldg. 10, CRC 5W-3888
Bethesda, MD 20892-1456
Phone (301) 451 8971
Fax (301) 451 7901
Cell (240) 361 7617
Pager 102 10678
srosenzweig at niaid.nih.gov
 
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>>> "Giclas, Patsy" <GiclasP at NJHealth.org> 06/07/11 12:51 AM >>>

Dear Sergio,

There are, as others have suggested, several explanations for the complement findings in this patient. If all three proteins are low, it pretty much rules out a genetic mechanism.  The genes for the 3 chains of C1q are on chromosome 1p34-1p36.3, those for C1r and C1s are in tandem, head to tail, on chromosome 12p13, while there are genes for C4 (A and B) and for C2 in the Class III MHC region at 6p21.3.  While there have been cases of combined C4 and C2 deficiency, including C1 in this scenario is highly unlikely. 

Activation is one likely possibility, but before chasing after complement activation products, it would be useful to know whether the C1, C2 and C4 are detectable in functional assays (hemolytic).  If not, and all 3 are low or nonfunctional, then looking for C4a, C4d, C3a or iC3b would be one way of determining if the parent proteins are being produced but cleaved before they can accumulate in the circulation.  The normal AH50 rules out the late components (C5 to C9), also including to a large extent, C3.  It is also unlikely that the control proteins H and I are missing or dysfunctional in this case.  The control proteins for the classical pathway include C1-Inhibitor and C4b-binding protein.  The former controls the cleavage of C4 by inactivating C1s, while the latter (with factor I) controls the cleavage of C3 by dissociating C4bC2a.  The lack of significant C3 cleavage (what was the actual C3 concentration?) is suggestive of fluid phase activation so you need to think of a non-particulate activator like small CIC (which test was negative?), low concentrations of cyroglobulins (causing ex vivo activation), possible viral or bacterial antigens or lipid-A rich endotoxins or the like. 

An experiment can be done by mixing the patient's serum with that of a normal, incubating it at 37 deg C for half an hour and then measuring the C4a and C3a that exist after the incubation.  The assumption is that if there is something in the patient's serum that is perpetuating the activation, it will cleave the proteins in the normal serum in a dose-dependent fashion.  Then you know something is there and can try to identify it better.

I don't want to go on into more nebulous territory, but please feel free to call or email me if you want to talk about it.

Thanks,

Patsy                                         

Patricia C. Giclas, PhD
Director, Diagnostic Complement Laboratory
Professor, Pediatric Allergy and Immunology
National Jewish Health
1400 Jackson
Denver Colorado, 80206 USA
-------------------------------
office 303-398-1217
Fax 303-270-2128
email giclasp at njhealth.org
Cell: 303-808-8958


________________________________________
From: pagid-bounces at list.clinimmsoc.org [pagid-bounces at list.clinimmsoc.org] On Behalf Of Sergio Rosenzweig [srosenzweig at garrahan.gov.ar]
Sent: Monday, June 06, 2011 3:45 PM
To: pagid at list.clinimmsoc.org
Subject: [CIS-PAGID] Complement sequencing

Dear All,
Are you aware of any commercial labs doing Complement (C1, C4, C2) sequencing (in or outside the US)?

Brief story: Previously healthy 60yo male starting 2.5y ago with 3 consecutive  episodes (within 6m) of high fevers, elevated LFTs and acute lung bilateral infiltrates/distress that took him to the ICU twice (no vent necessary), improved on IV antibiotics but no microorganisms were ever isolated. Serologies were neg or non contributory, in the context of NL Ig levels and adequate response to protein and polysaccharide antigens. Interestingly, CH50 has remained undetectable since the 1st time checked 2y ago, AP50 is normal, C1, C4 and C2 are very low or undetectable, CIC always normal, no skin, GI or renal disease, no autoab detected, SedRate and CPR WNL, and no Ig or C deposits at lung, liver or skin biopsies. After the original 3 episodes he repeated 2 more, just with high fevers and transient LFT elevation. Never placed on steroids, currently on prophylactic azithromycin since 1y ago.
Comments, questions and suggestions are more than welcome.
Thanks,
Sergio


Sergio D. Rosenzweig, MD, PhD
Chief, Infectious Diseases Susceptibility Unit
Laboratory of Host Defenses, NIAID, NIH
10 Center Dr., Bldg. 10, CRC 5W-3888
Bethesda, MD 20892-1456
Phone (301) 451 8971
Fax (301) 451 7901
Cell (240) 361 7617
Pager 102 10678
srosenzweig at niaid.nih.gov

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