Blood, 1 October 2002, Vol. 100, No. 7, pp. 2677-2678
CORRESPONDENCE
To the editor:
Autoimmunity in severe combined immunodeficiency
(SCID)
Arkwright et al1 are to be complimented for their
review on autoimmunity in human primary immunodeficiency diseases.
While they emphasized the role of opportunistic infections, which are common in primary immunodeficiency (PID) states in the development of
autoimmune disorders, we would like to draw attention to a completely
different pathogenic pathway. Indeed, the apparent paradox of
immunodeficiency and autoimmunity coexisting in the same patient is not
a real one. Recently, Candotti et al2 pointed out that
many components of the immune system have complex functions, which
often play both positive and negative roles.
In order to illustrate this point, we would like to report on 2 cases of severe combined immunodeficiency (SCID) with autoimmune diseases. SCID was not mentioned in Arkwright et al's review as a
predisposing condition to autoimmunity. Furthermore, at this young age,
opportunistic infections do not seem to be related to the autoimmune
phenomena. In both cases, stem cell transplantation corrected both the
immunodeficiency and the autoimmune conditions.
The first patient is a 2-month-old boy whose condition
was diagnosed as Omenn syndrome. Genetic analysis revealed a
1886C>T mutation in RAG1. At diagnosis
he had extended erythrodermia with scaling on his entire body.
He also had no hair on his scale or body as is described in Omenn
syndrome. Immunophenotyping from peripheral blood showed CD3 93%, CD20
2%, CD4 28%, and CD8 68%. Proliferation studies revealed
marked decreased response to various mitogens. Immunoglobulin levels
were very low for IgA, IgG, and IgM, whereas the IgE level was
increased to 74 IU. Skin biopsy was compatible with Omenn syndrome. No
melanocytes were seen at that time. The patient, aged 2 months,
received haploidentical peripheral stem cell transplants from his
father. This was done using T-cell depletion by positive
selection of CD34 cells by immunomagnetic beads. Conditioning included
busulphan 16 mg/kg, cyclophosphamide 200 mg/kg, fludarabine 200 mg/m,2 and anti-thymocyte globulin (ATG)
(fresenius) 25 mg/kg. No graft-versus-host disease prophylaxis
was given after transplantation. After rejecting the graft, he received
his second haploidentical transplants with T-cell depletion from his
mother. Conditioning included anti-CD3 (OKT3) and
thiotepa 7 mg/kg. Engraftment occurred on day +9 with complete donor
chimerism. Gradually, the erythrodermia subsided and he was noted to
have fair skin with white hair and white eyelashes
a picture
that resembled vitiligo. No other signs of graft-versus-host disease
(GVHD) were seen, and there were no gut or liver manifestations. Skin
biopsy was compatible with vitiligo with melanocytes and no evidence of
GVHD. Later, focal hyperpigmentation on exposed portions of his body
(face, hands, and legs) started to appear with coalescence of those
focal pigmentations into complete repigmentation thereafter. Also,
focal pigmentation appeared on the scale, with brown hair arising from
those spots later. A biopsy done from areas of pigmentation and
depigmentation showed melanocytes on pigmented areas and a lack of them
on the depigmented areas. Neonatal autoimmune disorder not related to
maternal disease is very rare.3 Because vitiligo is an
immunologic phenomena caused by activated T cells,4 we
hypothesized that a T-cell-mediated autoimmune process caused the
disappearance of melanocytes and vitiligo. This was corrected by stem
cell transplantation, causing elimination of the autoreactive T cells
that are common in Omenn syndrome.5 Now, 18 months after
transplantation, he has brown hands and his lower legs and face are
spotted with brown hair, whereas the rest of his body is only spotted
by pigmentation.
The second patient was diagnosed at the age of 11 months as
suffering from SCID with no T cells but with B and natural killer (NK)
cells (T-B+NK+) resulting from IL-7 receptor
alpha deficiency. The mutation found was a g-to-a base
substitution causing a splice-site mutation at position 
1 of
intron 2 leading to complete skipping of exon 3. At diagnosis
she had fever and diarrhea caused most probably by viral disease.
Later, she developed severe thrombocytopenia (5000/mm3) with wet purpura. Bone marrow
aspiration revealed increased number of megakaryocytes compatible with
the diagnosis of idiopathic thrombocytopenia purpura (ITP)
with no response to intravenous immunoglobulin (IVIG) and pulse
steroids. Allogeneic bone marrow transplantation from a matched-sibling
donor without conditioning or GVHD prophylaxis was performed. Two weeks
after transplantation there was a gradual increase in
thrombocyte numbers until full recovery. We concluded that this
patient's ITP was corrected by allogeneic bone marrow transplantation.
In summary, we reported on 2 infants with SCID and autoimmune
disorders. Both conditions were corrected by stem cell transplantation. As is stated in Candotti et al's paper, immunodeficiency and
autoimmunity are not opposites. Indeed, mixed pictures could happen.
Either way, stem cell transplantation is probably the correct solution for both problems.
Ronit Elhasid, Reuven Bergman, and Amos Etzioni
Correspondence: Amos Etzioni, Meyer Children's Hospital, Rambam
Medical Center, B. Rappaport School of Medicine, Technion, Haifa,
Israel 31096; e-mail: etzioni{at}rambam.health.gov.il
References
1.
Arkwright PD, Abinun M, Cant AJ.
Autoimmunity in human primary immunodeficiency diseases.
Blood.
2002;99:2694-2702[Abstract/Free Full Text].
2.
Candotti F, Notarangelo L, Visconti R, et al.
Molecular aspects of primary immunodeficiencies: lessons from cytokine and other signaling pathways.
J Clin Invest.
2002;109:1261-1269[CrossRef][Medline]
[Order article via Infotrieve].
3.
Bergman R, Sujov P, Peled M, et al.
Primary persistent autoimmune disorder in a neonate.
Lancet.
1999;353:124[Medline]
[Order article via Infotrieve].
4.
Kemp EH, Waterman EA, Weetman AP.
Autoimmune aspects of vitiligo.
Autoimmunity.
2001;34:65-77[Medline]
[Order article via Infotrieve].
5.
de Saint-Basile G, Le Deist F, de Villartay JP, et al.
Restricted heterogeneity of T lymphocytes in combined immunodeficiency with hypereosinophilia (Omenn's syndrome).
J Clin Invest.
1991;87:1352-1359[Medline]
[Order article via Infotrieve].
Response:
Redefining autoimmunity in primary immunodeficiency
diseases
Schuster et al's letter questioning our definition of
autoimmunity focuses in on the fundamental impetus for our
review.1 They are correct when they quote that
autoimmune disease is conventionally defined as a clinical syndrome
caused by the activation of T cells or B cells, or both, in the absence
of an ongoing infection or other discernible cause.2
However, in patients with autoimmunity associated with defined primary
immunodeficiency diseases (PIDs), advances in our understanding of the
disease pathogenesis means that this definition has been superseded.
Autoimmunity occurring in PIDs, although associated with immune
self-destruction, is not usually triggered by immune intolerance to
self-antigens. Autoimmune responses to self-antigens may contribute
to ongoing inflammation, but the primary trigger is generally the
inability of an inherently defective immune system to eradicate
persisting foreign microbial antigens. The basic principles underlying
the wide-spread tissue destruction in hemophagocytic
lymphohistiocytosis (HLH) syndromes, where defined underlying defects
in the immune system allows intercurrent Epstein-Barr virus
(EBV) infection or other factors to trigger uncontrolled
lymphocyte-initiated macrophage activation, are no different
to those seen in other autoimmune conditions associated with
PID.3 At the moment, we lack the knowledge to explain the
underlying immune mechanism(s) in many autoimmune
disorders,4 but there is no doubt that better understanding of the basis of autoimmunity in PID will provide a
framework for rethinking fundamental concepts as well as treatment strategies for these conditions.5,6
In their letter, Elhasid et al rightly point out that autoimmune
phenomena may develop in some cases of severe combined immunodeficiency (SCID). As detailed in our review,1 autoimmune phenomena
are well recognized in Omenn syndrome. Certain mutations in the
RAG gene result in incomplete blockage of T-lymphocyte
development. Dysfunctional T-cell clones may cause inflammation in any
tissue of the body, but especially in the skin, liver, bone marrow, and brain.7 Other formes frustes of SCID with aberrant
T-lymphocyte development, often presenting in older children or adults
as common variable immunodeficiency, may also be associated with
clinically significant autoimmunity.1,3,8 In contrast, in
children with classical SCID in whom no T lymphocytes are present,
clinical features suggestive of autoimmunity are more likely to be due to the direct consequences of infections, as the complete lack of T
lymphocytes prevents the development of an autoimmune response. Elhasid
et al's second patient with
T
B+NK+ SCID developed a
consumptive thrombocytopenia that did not respond to steroids or
high-dose intravenous immunoglobulin (IVIG) therapy, but the patient
did finally respond to matched-sibling bone marrow transplantation.
Considering the temporal relationship to the other symptoms of viral
infection, it is likely that rather than the thrombocytopenia being
ITP, it was directly caused by the virus infection. As emphasized in
our review, immunomodulation and treatment of infection is often a
better treatment strategy than immunosuppression alone in children with
primary immunodeficiency and suspected autoimmune phenomena, as
immunosuppression may exacerbate the underlying infectious disease and
result in increased morbidity and mortality.
Finally, as stated in our review and reiterated by Elhasid et al,
in children with an underlying PID, autoimmunity and the inability to
effectively eradicate infection should both be viewed as features of
dysregulated immunity. Correcting the underlying immunodeficiency by
stem cell transplantation often corrects both clinical problems.
Although stem cell transplantation had in the past been considered, but
not often used, as a possible treatment option for autoimmunity where
no underlying primary immunodeficiency can be found, advances in the
safety and effectiveness of this therapy have recently lead to a
revival in interest in this treatment modality.9
Peter D. Arkwright, Mario Abinun, and Andrew J. Cant
Correspondence: Peter D. Arkwright, Academic Unit of Child
Health, St Mary's Hospital, Hathersage Road, Manchester, M13 0JH,
United Kingdom; e-mail: peter_arkwright{at}lineone.net
References
1.
Arkwright PD, Abinun M, Cant AJ.
Autoimmunity in human primary immunodeficiency diseases.
Blood.
2002;99:2694-2702[Abstract/Free Full Text].
2.
Davidson A, Diamond B.
Autoimmune Diseases.
N Engl J Med.
2001;345:340-350[Free Full Text].
3.
Candotti F, Notarangelo L, Visconti R, O'Shea J.
Molecular aspects of primary immunodeficiencies: lessons from cytokine and other signaling pathways.
J Clin Invest.
2002;109:1261-1269[CrossRef][Medline]
[Order article via Infotrieve].
4.
de Saint Basile G, Fischer A.
The role of cytotoxicity in lymphocyte homeostasis.
Curr Opin Immunol.
2001;13:549-554[CrossRef][Medline]
[Order article via Infotrieve].
5.
Fairweather D, Kaya Z, Shellam GR, Lawson CM, Rose NR.
From infection to autoimmunity.
J Autoimmun.
2001;16:175-186[CrossRef][Medline]
[Order article via Infotrieve].
6.
Panoutsakopoulou V, Cantor H.
On the relationship between viral infection and autoimmunity.
J Autoimmun.
2001;16:341-345[CrossRef][Medline]
[Order article via Infotrieve].
7.
Villa A, Sobacchi C, Notarangelo LD, et al.
V(D)J recombination defects in lymphocytes: a severe immunodeficiency with a spectrum of clinical presentations due to RAG mutations.
Blood.
2001;97:81-88[Abstract/Free Full Text].
8.
Fischer A.
Primary immunodeficiency diseases: an experimental model for molecular medicine.
Lancet.
2001;357:1863-1869[CrossRef][Medline]
[Order article via Infotrieve].
9.
Good RA, Verjee T.
Historical and current perspectives on bone marrow transplantation for prevention and treatment of immunodeficiency and autoimmunity.
Biol Blood Marrow Transplant.
2002;7:123-135.
