Circulating immune complexes

[Arfmeister]

I’m trying to look for a possible lead:

I recently had high blood-measurements of Circulating Immune Complexes (CIC) at 2 different time points

• Early September : 130 (reference range 0-20)
• Half October : 78 (range 0-20)
  • October was AFTER a immune suppressive treatment

Note:
Circulating immune complexes are antigen–antibody complexes normally cleared by:
• Complement system
• Liver & spleen
When clearance fails, complexes circulate and deposit in tissues.

It’s not used as a standalone marker. Specialist interpret CIC together in conjunction with:
• Symptoms and Disease context
• And markers : Complement levels (C3, C4)
• Inflammatory markers (ESR, CRP) ⇒ these were normal within range btw
***

My clinician did not know what it implied, but that it is immune related.
As far as I understand, it is common in lupus, R.A. Sjögren’s syndrome, and some other conditions and chronic infections.

There is very little to be found about Immune Complexes and ME

My questions:

1. Anyone else had CIC measured?
2. Is this a possible lead for further investigation or a potential diagnosis / comorbidity?
3. What other test would you advise?

*PS attachment: chatGTP made an overview as an explanation CIC
(so I cannot vouch for the correctness)

 

[Arfmeister]

I have found these 3 articles :

1) A 1994 German study found circulating immune complexes in 42% of investigated CFS patients, alongside other markers like elevated TNF-α
<https://pubmed.ncbi.nlm.nih.gov/7856214/ >

2) A 1995 U.S. study of 579 CFS patients (compared to controls) showed significantly elevated circulating immune complexes (adjusted odds ratio: 26.5)
<https://pubmed.ncbi.nlm.nih.gov/7632202/ >

3) a 1991 review noted low levels of circulating immune complexes as a common finding in CFS, and some case-control studies found no significant differences.
<https://pubmed.ncbi.nlm.nih.gov/1902321/>

 

[Jonathan Edwards]

We need to know what assays are being used. Things have moved on from the days of circulating immune complex assays that anyone believed (the 1970s). Most of the old assays depend on complement engagement or artifactual precipitation conditions and may just have measured Ig levels as much as anything.

Do you have any idea what assay was used?

Immune complexes are probably very important in several diseases but for quite different reasons in each disease. I don't see any clinical evidence of circulating immune complexes acting in ME/CFS though.

 

[Arfmeister]

Do you have any idea what assay was used?

The unit used: ED/mL
Reference range 0 to 20 ED/mL

Very likely a C1q binding ELISA

• I even have the LOINC code 27831-7I

Immune complexes are probably very important in several diseases but for quite different reasons in each disease

Yes. I was wondering if I could go with these results to a run-of-the-mill rheumatologist or immunologist to check if I have a secondary disease.
Or should I have a specific symptomology to go with it?

 

[Jonathan Edwards]

The unit used: ED/mL
Reference range 0 to 20 ED/mL

What does ED stand for?

I doubt C1q would be used in an ELISA since its binding is dependent on steric conformations in fluid phase?

 

[Jonathan Edwards]

Yes. I was wondering if I could go with these results to a run-of-the-mill rheumatologist or immunologist to check if I have a secondary disease.
Or should I have a specific symptomology to go with it?

For the last twenty years of my working life as a rheumatologist everyone completely ignored immune complex assays as meaningless. I suspect that continues.

If circulating complexes bind C1q they are taken up by red cell CR1 and cleared without ill effect. The fashion for immune complex assays was in the 1980s when nobody understood the role of complement in disease.

 

[Arfmeister]

What does ED stand for?

ED/ml stands for Equivalent Doses/ml
Like Units: µg Eq/mL or EU/mL

doubt C1q would be used in an ELISA since its binding is dependent on steric conformations in fluid phase?

I’m trying to find out. Very complicated to contact the lab (also lacking the capacity)

it’s definitely ELISA. My guess it’s either:
- C3d-Binding Assay
- C1q binding
They both have cut off points at ≥ 20 EU/ml

I will try to find more information

< https://kentri.testcatalog.org/show/FCIC >

 

[Arfmeister]

For the last twenty years of my working life as a rheumatologist everyone completely ignored immune complex assays as meaningless. I suspect that continues.

If circulating complexes bind C1q they are taken up by red cell CR1 and cleared without ill effect. The fashion for immune complex assays was in the 1980s when n

Bugger, So it probably won’t lead to any interest of a specialist ?

Do you also think it doesn’t really imply anything - with typical classic ME symptomology - without any other lab-data ?

 

[Jonathan Edwards]

Do you also think it doesn’t really imply anything - with typical classic ME symptomology - without any other lab-data ?

Yes, we realised in the 1980s that immunoglobulins will stick to complement components in plastic systems for all sorts of irrelevant reasons. I am amazed that these things are still offered. They may have got re-invented by people who are unaware why they were binned.

 

[Arfmeister]

Aside from the validity of the CIC test ( - I’m still waiting for more info on the exact test).

I was wondering the following.

Could it be that In ME/CFS, immune complexes can be understood in a different way?

• Instead of pointing to classic autoimmune damage, they reflect a situation where antigens are still present because the immune system is not fully clearing them
• The immune system may still be detecting danger and staying alert, but its ability to fully eliminate microbes is weakened
• As a result, material from viruses that reactivate, bacteria that live inside cells, or products coming from the gut can keep stimulating the immune system
• This can happen even when common inflammation markers like CRP or ESR are normal

In this situation, immune complexes are not a marker for disease

• Instead, they act like a biological trace showing that the body and the microbes are stuck in a long-term standoff
• The immune system stays switched on at a low level, but becomes exhausted or overly tolerant, allowing antigens to persist and repeatedly activate innate immune sensors

 

[Jonathan Edwards]

Could it be that In ME/CFS, immune complexes can be understood in a different way?

We all have antibodies binding to microbial junk antigens all day and night. It slips under the radar because the complexes are cleared. So yes, this is possible.

'Immune complex' is a rather vague term and has led to huge confusion. It can just mean an antibody bound to an antigen in solution or with complement components attached or bound in solid phase or an intermediate 'colloidal phase' which would apply to free viruses coated with antibody.

Immune complex assays try to find complexes in solution, mostly without complement already there but it depends on the assay.

Normally antigen in circulation binding to antibody fixes C1q and is cleared by ared cell within a micrometer more or less immediately. That can fail but you need special conditions.

The idea we put in Qeios was that antigen was binding to antibody that was already fixed to macrophae FCR1 receptors. The output there is different