[CIS PIDD] [cis-pidd] TACI and autoimmunity

Thu Dec 22 14:00:05 EST 2016

Hi Ashish,

If you have CVID, the presence of the heterozygous C104R mutation is associated with a 2 fold increase in autoimmune disease, especially autoimmune cytopenias (Salzer et al, Blood 2009). I don’t know of any data suggesting the C104R mutation is associated with autoimmune disease in the absence of humoral immune deficiency.

If your patient is a CVID patient, then I think her C104R TACI mutation likely explains her cytopenias. In terms of therapy, if she is on antibody replacement therapy already, rituximab is a great option.

‘best

Neil

Neil Romberg, MD
Jeffrey Modell Chair of Pediatric Immunology Research
Attending Physician, Children’s Hospital of Philadelphia
Assistant Professor of Pediatrics, University of Pennsylvania
Abramson Suite 1216C
3615 Civic Center Blvd.
Philadelphia, PA 19104
(p) 267-426-8195
(f) 267-426-0363
www.romberglab.org

From: CIS-PIDD <cis-pidd at lists.clinimmsoc.org>
Reply-To: CIS-PIDD <cis-pidd at lyris.dundee.net>
Date: Thursday, December 22, 2016 at 12:59 PM
To: CIS-PIDD <cis-pidd at lyris.dundee.net>
Subject: RE: [cis-pidd] TACI and autoimmunity

While we’re on the subject of TACI, I have a patient who is heterozygous for the C104R mutation/change. She is 11 years old and has had recurrent autoimmune cytopenias since the age of 3. Her father is also heterozygous but totally asymptomatic. We even ran whole exome trios and this was the only finding that came out. She has autoimmune hemolytic anemia or thrombocytopenia about once a year. Has anyone used maintenance immune suppression in such cases – Sirolimus or other? She is only 11, so the risk is not trivial.
Ashish
Ashish Kumar, MD, PhD
Associate Professor of Pediatrics
Director, Langerhans Cell Histiocytosis Center
Director, Pediatric Hematology/Oncology Fellowship Program
Cincinnati Children's
3333 Burnet Avenue, , Cincinnati, OH 45229

[ttps://www.cincinnatichildrens.org/-/media/295b830c6eb94ee2b662c61a2945e5e6.ashx?h=67&w=200]<https://www.cincinnatichildrens.org/>

From: CIS-PIDD [mailto:cis-pidd at lists.clinimmsoc.org]
Sent: Wednesday, December 21, 2016 7:26 PM
To: CIS-PIDD <cis-pidd at lyris.dundee.net>
Subject: Re: [cis-pidd] TACI and autoimmunity

Dear Peter,

Eric Meffre and I published a paper last year in JACI (PMID: 26100089) on the immunologic consequences of TACI hemizygosity. We studied CVID patients with TACI null mutations (similar to your patient’s mutation) and patients who lost one TACI allele to a chromosomal deletion. Unlike CVID patients with classic TACI missense mutations who have lots of autoimmune diseases, our subjects had none. We’ve now studied nearly 80 of these patients and found a very low incidence of autoimmune disease.

Accordingly, I don’t think you can attribute your patient’s autoimmune features to her TACI mutation.

I hope this helps,

Neil

Neil Romberg, MD
Jeffrey Modell Chair of Pediatric Immunology Research
Attending Physician, Children’s Hospital of Philadelphia
Assistant Professor of Pediatrics, University of Pennsylvania
Abramson Suite 1216C
3615 Civic Center Blvd.
Philadelphia, PA 19104
(p) 267-426-8195
(f) 267-426-0363
www.romberglab.org<http://www.romberglab.org>

From: CIS-PIDD <cis-pidd at lists.clinimmsoc.org<mailto:cis-pidd at lists.clinimmsoc.org>>
Reply-To: CIS-PIDD <cis-pidd at lyris.dundee.net<mailto:cis-pidd at lyris.dundee.net>>
Date: Wednesday, December 21, 2016 at 4:36 PM
To: CIS-PIDD <cis-pidd at lyris.dundee.net<mailto:cis-pidd at lyris.dundee.net>>
Subject: [cis-pidd] TACI and autoimmunity

Dear all,

We would appreciate your advice regarding a 28 year old woman with several autoimmune features: dactylitis, celiac disease, autoimmune thyroiditis and multiple sclerosis. No remarkable infections so far. She is currently under the care of our adult rheumatologist and more or less controlled with intermittent corticosteroids and teriflunomide.

Her most recent immunological data:
Normal number of T and B cells
Lowish NK cell numbers
Normal IgG (including subclasses), IgA and IgM levels, normal vaccine response (only total IgG2 levels for Pneumococcus available)

- 15,64% Tregs: CD4+/CD25+ of T CD4+, 0,79% with FoxP3 expression
- 9,85% TH17 CD4+/CD161+/CD196 of T CD4+ (and 2,04% of total lymphocytes)

- B cell panel:
   - 44,43%  (CD19+/IgD+/CD27-),
   - 47,00% (CD19+/CD27+)
   - 12,81%  (CD19+/IgD+/CD27+),
   - 34,19% (CD19+/IgD-/CD27+)
   - 8,56% (CD19+/IgD-/CD27-)
Transitional B cells: 6,47% d
CD21 low: 5,54%
Plasmablasts: 2,18% (2660 células/ml)

 CD4+/CD45RA+/CD45RO-: 39,91%
 CD4+/CD45RA-/CD45RO+: 40,39%
 CD4+/CD45RA+/CD45RO+: 18,31%
 CD8+/CD45RA+/CD45RO-: 61,41%
 CD8+/CD45RA-/CD45RO+: 19,77%
 CD8+/CD45RA+/CD45RO+: 15,81%
 CD4+/CD38+: 38,99%
 CD4+/HLA-DR+: 6,09%
 CD4+/CD38+/HLA-DR+: 1,64%
 CD4+/CD38-/HLA-DR-: 34,51%
 CD8+/CD38+: 61,14%
 CD8+/HLA-DR+: 14,00%
 CD8+/CD38+/HLA-DR+: 7,23%
 CD8+/CD38-/HLA-DR-: 32,09%

We included her in our in-house PID chip (IonTorrent platform) and found a heterozygous mutation in TACI with a stop codon just in the beginning of the gene (p.Arg9Ter), later confirmed by Sanger. No mutations were identified in other "candidate genes" such as CTLA4, LRBA, PIK3, STAT1, STAT3,..

Her father also carries the same mutation but he is completely asymptomatic. All other tested family members are asymptomatic and tested negative for the mutation.

We would appreciate your opinion regarding this "finding" and wonder if someone has been involved in the care of TACI patients with similar clinical/lab features (progressive autoimmune manifestations, low Tregs but apparently normal antibody production).

Many thanks in advance for your thoughts!

Peter Olbrich
FEA Pediatría
Infectologia Pediátrica e Inmunopatologias
H.U. Virgen del Rocío Sevilla
SPAIN

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