Discussion
CVID represents one of the most common primary antibody deficiency which
is associated with a broad spectrum of non-infectious complications
including various autoantibody-mediated autoimmune diseases. Several
studies reported the presence of various antibodies directed against
“self-antigens”, such as feritin, thyreoglobulin or DNA in the
therapeutics used for IRT (12).
Antierythrocyte alloantibodies or anti-Ro (SS-A) were even associated
with clinical manifestation – self-limiting hemolysis
(11) and sicca syndrome
(13). Thefore, we initiated the
prospective observational study focusing on the prevalence, clinical
significance and the origin of selected spectrum of autoantibodies in a
cohort of 38 CVID patients treated with regular IRT.
Anti-GAD and anti-TPO were the most prevalent autoantibodies found in
the majority of CVID patients on regular IRT (68.4% and 55.3%,
respectively). All other investigated autoantibodies including ANA,
anti-dsDNA, anti-EMA, RF, ACLA, anti-F-actin, anti-SLA, anti-LKM1,
anti-LC1, anti-AMAM2, anti-MPO, anti-PR3, anti-Sm, anti-RNP, anti-SS-A,
anti-SS-B, anti-Scl70, anti-Jo-1, anti-IAA, anti-IA2 and anti-TG were
negative in all patients, with exception of anti-TG, anti-IAA and
anti-IA2 found in patients with previously diagnosed T1D and AIT at the
screening visit, who were excluded based on exclusion criteria.
Interestingly, both excluded CVID patients with T1D were anti-GAD
negative. However, the titers of anti-GAD observed in our cohort of CVID
patients were significantly lower in comparison to newly diagnosed T1D
patients. The cohort of CVID patients was prospectively followed to
assess the T1D development. This included regular measurements of
fasting C-peptide as a marker of inzulin production and g-Hgb reflecting
long-term glycemia. No differences were found in serum concentration of
C-peptide and g-Hgb between anti-GAD negative and positive CVID
patients, as well as between the baseline and end-of-study visits in
anti-GAD positive patients. On the other hand, the serum levels of
C-peptide were significantly higher and the levels of g-Hgb
significantly lower in comparison to newly diagnosed T1D patients
suggesting an undisturbed inzulin production and glucose metabolism.
Similarly, the serum titers of anti-TPO autoantibodies in CVID patients
were also significantly lower than in newly diagnosed AIT patients.
However, no differences were found in the serum levels of TSH and fT4
between anti-TPO positive, anti-TPO negative CVID patients and AIT
patients. Both paramters were within referential limits in all groups.
Therefore, the thyroid gland USG was performed to evaluate the presence
of predictive signs of subclinical AIT
(14). Based on the USG, the diagnosis of
AIT was considered in three out of 26 anti-TPO positive patients and in
one patient without AIT specific autoantibodies.
The same spectrum of autoantibodies was also assessed in IRT
therapeutics. Surprisingly, all solutions contained high amount of
anti-GAD and anti-TPO autoantibodies. Other investigated autoantibodies
were uniformly negative. The possible explanation for this phenomenon
may be found in population-based studies investigating the prevalence of
anti-GAD and anti-TPO. Anti-GAD autoantibodies were present in 0.9 –
1.7% of healthy donors, the highest prevalence 3.2% was observed in
age group 30-34 years (15). Even higher
prevalence was reported for anti-TPO antibodies – up to 31.7% of
healthy donors (16,
17). Based on our findings and the
previously published reports, we therefore suggest that these
autoantibodies may be passively transfered into blood circulation via
the immunoglobulin solutions. Our findings are also consistent with
previous observations that T1D and AIT are predominantly T-cell-mediated
diseases (18-21). Correspondingly, both
T1D and AIT may develop in the abscence of specific autoantibodies. The
autoantibody negative cases comprise 3.5-19% from all T1D patiens
(22, 23),
moreover, several seronegative T1D patients were also desribed amongst
the CVID patients (10). Autoantibody
negative AIT represents approximately 5% of all patients with AIT
(24). While the tissue specific
autoantibodies may not constitute the principal pathophysiological
mechanisms in T1D and AIT, they represent a commonly used diagnostic and
prognostic marker. The physicians should therefore be sensitized to the
fact, that in CVID patients on regular immunoglobulin subtitution
therapy neither serum anti-GAD nor anti-TPO are suitable tools for the
screening or diagnosis of T1D or AIT.
The authors are aware, that due to the limitations of this pilot study,
the results must be interpreted with caution. The strength of the study
is particularly in its prospective design and the utilization of routine
and certified laboratory methods. On the other, the limited number of
included patients and the relatively short trial follow up time are its
main limitations. Further multicentric and longer follow up studies are
warranted to confirm these findings.