[PAGID] PAGID Digest, Vol 36, Issue 7

[Jennifer Puck]

Have people come across patients with lupus who presented with, or
developed, this degree of T lymphocytopenia?
There are reports, including Yu et al., Rheumatology (Oxford). 2007
Sep;46(9):1492-4. Epub 2007 Aug 1. of <500 lymphocytes at presentation in a
proportion of pediatric lupus at presenetation; also lymphocytopenia was
associated with lupus flares, organ damage, and particularly neuro
involvement.
Jennifer

Jennifer M. Puck, M.D.
Professor of Pediatrics
University of California, San Francisco, Box 0519
513 Parnassus Avenue, HSE 301A
San Francisco, CA  94143-0519

Email: puckj at peds.ucsf.edu
Phone: 415 476-3181
FAX: 415 502-5127 



On 4/21/08 9:13 AM, "pagid-request at list.clinimmsoc.org"
<pagid-request at list.clinimmsoc.org> wrote:


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> Today's Topics:

> 

>    1. Re: Patient with lymphopenia (Luigi Notarangelo)

>    2. Re: Patient with lymphopenia (Jack Bleesing)

>    3. Re: Patient with lymphopenia (Marc Riedl)

> 

> 

> ----------------------------------------------------------------------

> 

> Message: 1

> Date: Mon, 21 Apr 2008 08:43:59 -0400

> From: "Luigi Notarangelo" <luigi.notarangelo at childrens.harvard.edu>

> Subject: Re: [PAGID] Patient with lymphopenia

> To: pagid at list.clinimmsoc.org

> Message-ID: <C4320450.A910%luigi.notarangelo at childrens.harvard.edu>

> Content-Type: text/plain; charset="iso-8859-1"

> 

> Dear Jason:

> 

> Indeed, a very interesting patient.

> 

> While idiopathic CD4 lymphopenia would have to be considered, as already

> mentioned by others, I agree with Dale Umetsu that any form of ?leaky SCID?

> might result in a similar phenotype.

> A few years ago, we reported on a family with JAK3 deficiency in which late

> diagnoses were made based on warts and lymphopenia (Frucht et al, Genes and

> Immunity, 2001; 2:422) in some, but not all, affected family members.

> I agree with Melvin that functional assays would be important in a case like

> yours. One way to overcome the issue of T cell lymphopenia would be to label

> in vitro cells with CFSE prior to the culture and then follow specifically

> proliferation of the T cells in response to PHA (and also to anti-CD3 alone

> or with IL-2) by looking at dilution of CFSE gating on the CD3+ population.

> You might even use this approach to investigate whether you have increased

> cell death during the culture, by staining for annexin V.

> 

> Very interesting! Please, keep us updated!

> 

> Gigi

> 

> 

> Luigi D. Notarangelo, M.D.

> Director, Research and Molecular Diagnosis Program on Primary

> Immunodeficiencies

> Division of Immunology, Children's Hospital

> Professor of Pediatrics and Pathology, Harvard Medical School

> Karp Building, 9th floor, Rm 09210

> 1 Blackfan Circle

> Boston, MA 02115

> USA

> 

> (tel) (617)-919-2276

> (fax) (617)-730-0709

> 

> 

> Secretary: Luisa Raleza

> email: luisa.raleza at childrens.harvard.edu

> 

> 

> 

> 

> 

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> ------------------------------

> 

> Message: 2

> Date: Mon, 21 Apr 2008 09:04:21 -0400

> From: "Jack Bleesing" <Jack.Bleesing at cchmc.org>

> Subject: Re: [PAGID] Patient with lymphopenia

> To: <pagid at list.clinimmsoc.org>

> Message-ID: <480C5895020000310001E9FB at n6mcgw16.cchmc.org>

> Content-Type: text/plain; charset=UTF-8

> 

> Morning Folks:

> 

> - Don't forget in vitro delayed skin tests as a functional T-cell

> function test (and bypassing the lack of CD4 T-cells)

> 

> - Would be interested in more detailed immunophenotyping of her lymphs

> (Forms Follows Function)

> 

> - PNP deficiency: screening tool = low to absent uric acid levels

> 

> - Atypical WHIM? (reduced naive and central memory T-cells, see

> Blood;102:444, 2004).

> 

> - B-cell phenotype/increased transitional?; IL-7 levels? (see Blood,

> 109;2086, 2007)

> 

> - we have seen several patients with "leaky SCID" phenotype with

> presumed mono-allelic IL-7R mutations and auto-immunity (true, true and

> unrelated?). Mono-allelic other SCID genes could be considered as well,

> as we have a fairly convincing CID patient with mono-allelic JAK3

> mutation (same as seen in classic SCID); fairly convincing because she

> might have something else as well - related to growth-hormone

> insensitive growth delay.

> 

> - autoantibodies to T-cells, as seen in SLE and ALPS (perhaps)?;

> preserved function and immunophenotypic clues

> 

> Regards,

> 

> J

> 

> ---------------------------------------------------------------------------

> Jack J.H. Bleesing, M.D., Ph.D.

> Cincinnati Children's Hospital Medical Center

> Division of Hematology/Oncology

> 3333 Burnet Avenue, MLC 7015

> Cincinnati, OH 45229

> 513-636-4266 (phone)

> 513-636-3549 (fax)

> Jack.Bleesing at CCHMC.org

> http://www.cincinnatichildrens.org/immunodeficiencies/

> 

> 

>>>> "Luigi Notarangelo" <luigi.notarangelo at childrens.harvard.edu>

> 4/21/2008 8:43 AM >>>

> Dear Jason:

> 

> Indeed, a very interesting patient.

> 

> While idiopathic CD4 lymphopenia would have to be considered, as

> already

> mentioned by others, I agree with Dale Umetsu that any form of ?leaky

> SCID?

> might result in a similar phenotype.

> A few years ago, we reported on a family with JAK3 deficiency in which

> late

> diagnoses were made based on warts and lymphopenia (Frucht et al, Genes

> and

> Immunity, 2001; 2:422) in some, but not all, affected family members.

> I agree with Melvin that functional assays would be important in a case

> like

> yours. One way to overcome the issue of T cell lymphopenia would be to

> label

> in vitro cells with CFSE prior to the culture and then follow

> specifically

> proliferation of the T cells in response to PHA (and also to anti-CD3

> alone

> or with IL-2) by looking at dilution of CFSE gating on the CD3+

> population.

> You might even use this approach to investigate whether you have

> increased

> cell death during the culture, by staining for annexin V.

> 

> Very interesting! Please, keep us updated!

> 

> Gigi

> 

> 

> Luigi D. Notarangelo, M.D.

> Director, Research and Molecular Diagnosis Program on Primary

> Immunodeficiencies

> Division of Immunology, Children's Hospital

> Professor of Pediatrics and Pathology, Harvard Medical School

> Karp Building, 9th floor, Rm 09210

> 1 Blackfan Circle

> Boston, MA 02115

> USA

> 

> (tel) (617)-919-2276

> (fax) (617)-730-0709

> 

> 

> Secretary: Luisa Raleza

> email: luisa.raleza at childrens.harvard.edu

> 

> 

> 

> 

> 

> 

> 

> ------------------------------

> 

> Message: 3

> Date: Mon, 21 Apr 2008 09:13:02 -0700

> From: "Marc Riedl" <mriedl at mednet.ucla.edu>

> Subject: Re: [PAGID] Patient with lymphopenia

> To: <pagid at list.clinimmsoc.org>

> Message-ID: <002b01c8a3ca$92cb08c0$b8611a40$@ucla.edu>

> Content-Type: text/plain; charset="us-ascii"

> 

> Jason,

> 

>  

> 

> We've seen a few such patients here as well.   I agree with many of the

> previous suggestions:

> 

> -          We typically perform in vivo DTH testing as well as in vitro

> proliferation assays

> 

> -          We have identified ADA deficiency in one case

> 

> -          However, most of the time we end up with a diagnosis of

> "idiopathic lymphopenia" having ruled out other potential causes

> 

> The good news is that in my experience, the vast majority of these patients

> do well clinically without serious life-threatening infections.

> 

>  

> 

> Regards,

> 

>  

> 

> Marc

> 

>  

> 

> Marc Riedl, M.D., M.S.

> Assistant Professor of Medicine

> Section Head, Clinical Immunology and Allergy

> UCLA - David Geffen School of Medicine

> 10833 Le Conte Ave, 37-131 CHS

> Los Angeles, CA  90095-1680

> Tel 310.206.4345  Fax 310.267.0090

> 

>  

> 

>  

> 

>  

> 

> From: pagid-bounces at list.clinimmsoc.org

> [mailto:pagid-bounces at list.clinimmsoc.org] On Behalf Of Jason Raasch, MD

> Sent: Sunday, April 20, 2008 6:42 PM

> To: pagid at list.clinimmsoc.org

> Subject: [PAGID] Patient with lymphopenia

> 

>  

> 

> Please offer your insight into this 53 year old woman with persistent

> verruca plantaris (plantar warts) and severe lymphopenia.  Consider the

> following questions as you review the case:

> 

>  

> 

> First note flow cytometry (presented in absolute numbers, gated on CD45):

> 

>  

> 

> Total CD3 lymphocytes: 53 per mm3 (reference 1064-1672)

> 

> CD3+CD4+: 10 (627-1102)

> 

> CD3+CD8+: 38 (247-741)

> 

> CD4:CD8 = 0.27

> 

> CD19:  93 (95-418)

> 

> CD56+16+: 93 (95-494)

> 

>  

> 

> At first glance, whether primary or acquired, this is striking.  Now

> consider her clinical history:  She was well from birth through adolescence.

> Varicella at age five; shingles at age 19.  Seizures at age 23; on

> Phenobarbital for 10 years this was then discontinued and she has had no

> further neurologic events.

> 

>  

> 

> By her late 20's she began having persistent verruca vulgaris on hands,

> knees, pre-tibial area and feet.  Over the last 30 years has failed OTC

> therapies as well as excision, laser ablation, cryotherapy, topical and oral

> retinoids and localized bleomycin.

> 

>  

> 

> Variably positive ANA (up to 1:320, but often undetectable) starting in her

> 30s.  Other than intermittent arthralgias, no other symptoms.

> Hypothyroidism diagnosed at age 51 (thyroglobulin and thyroperoxidase

> antibodies undetectable).

> 

>  

> 

> Lymphopenia brought to her attention at age 52 (WBC 4,000/mm3; ANC=3,200;

> ALC=240).  Medical record review actually demonstrates same findings as far

> back as 1970's and persistently each decade thereafter, suggesting a

> long-standing finding.

> 

>   

> 

> Review of systems completely unremarkable except for the above, as well as

> mild depression and hypothyroidism.  No GI symptoms.  No history of

> recurrent infection.  No history of heart disease or abnormal facies.

> Patient reports unremarkable family history.

> 

>  

> 

> Over the last 18 months the following have been UNREMARKABLE: electrolytes,

> ALT/AST, serum albumin and protein, B12, folate and iron levels, serum

> electrophoresis/immunofixation, quantitative immunoglobulins,

> tetanus/diphtheria, pneumococcal and varicella titers, isohemagglutinins,

> rheumatoid factor, dsDNA, CCP antibody, CRP, ESR, C3, C4, CH50, TSH and T4.

> Stool alpha-1 antitrypsin normal.  HIV ELISA X 2 negative.  FANA 1:40 with

> homogeneous pattern.

> 

>  

> 

> INTERESTINGLY, this patient reports that her HEALTHY adolescent daughter was

> incidentally found to have just as severe a lymphopenia AND neutropenia.

> 

>  

> 

> In summary this is a fairly health woman with a striking lymphopenia (that

> most likely has been present over the last 30+ years), persistent verruca

> vulgaris and intermittently positive ANA.  A HEALTHY daughter has

> lymphopenia and neutropenia and has not had evaluation.

> 

>  

> 

> So the questions:

> 

> 1. Who has seen cases like this?

> 2. Why has she had such a benign course despite such a lymphopenia?

> 3. To what extent should a diagnosis be pursued?  In her daughter?

> 

>  

> 

> I am interested in any comments.

> 

>  

> 

> Have a great week.

> 

>  

> 

> --jason

> 

>  

> 

> Jason P. Raasch, MD

> 

> Children's Hospitals and Clinics of Minnesota

> 

>  

> 

> Midwest Immunology Clinic

> 

> 2805 Campus Dr, #215

> 

> Plymouth, MN 55441

> 

>  

> 

> Telephone: 763.577.0008

> 

> FAX: 763.577.0192

> 

> e-mail: raas0027 at umn.edu

> 

>  

> 

> 

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> End of PAGID Digest, Vol 36, Issue 7

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