Introduction
Primary immunodeficiencies (PIDs) are a heterogeneous group of inherited disorders of the immune system leading to enhanced susceptibility to infections [
1]. The complement system is a crucial component of innate immunity and one of the main effector mechanisms of antibody-mediated immunity (reviewed in [
2]).
Inherited complement deficiencies represent immunodeficiencies characterized by susceptibility to invasive infections by encapsulated bacteria such as
Streptococcus pneumoniae (reviewed in [
3‐
5]). The third component of the complement system (C3) is indispensable to all the known pathways of complement activation. C3 deficiency (OMIM
: 120700) is a rare PID, leading to predisposition to recurrent pyogenic infections [
1,
4].
A few biallelic defects in the
C3 gene have been described in patients suffering not only from
S. pneumoniae infections [
6‐
12] but also from autoimmune and immune-complex-related disorders, in particular affecting the kidney [
13‐
15]. A similar phenotype can also be observed in patients with deficiency of complement factor H or I, respectively [
5].
Here, we describe a patient with selective immunoglobulin A (IgA) deficiency presenting with recurrent airway infections caused by S. pneumoniae and bronchiectasis with no autoimmune or immune complex manifestations. Our molecular analyses revealed that the patient suffers from C3 deficiency caused by a novel, homozygous mutation in the C3 gene.
Discussion
The complement system is a protein network crucial for both innate and adaptive immune responses. C3 is the convergence point for all the known complement activation cascades, resulting in cleavage of C3 into C3a (anaphylatoxin) and C3b (reviewed in [
2]). The latter is an important product for opsonization of bacteria including encapsulated bacteria such as
S. pneumoniae [
18,
19], for amplification of complement activation through the alternative pathway, where the association of C3b with complement factor B is essential, and for cell lysis through the formation of C5 convertase (reviewed in [
2]). Patients with C3 deficiency frequently develop severe episodes of recurrent pneumonia, meningitis or sepsis. Clinically, these patients present at an early age with overwhelming infections caused by
S. pneumoniae [
4,
5]. Autoimmunity and other immune manifestations, frequently affecting the kidney, are also observed in C3-deficient patients [
13‐
15].
Since the parents of the patient described here were first-degree cousins and the index patient’s severe clinical manifestations were unlikely to be explained by the diagnosis of isolated IgA deficiency, an autosomal recessive disorder was suspected. We discovered and here describe a novel, homozygous missense mutation in
C3, altering a highly conserved amino acid found in the first position of the C345C domain of the C3 protein which is hypothesized to function as a binding site for factor B, as required for C3 convertase formation [
20‐
22]. This domain is known to undergo large rearrangements upon activation and is present in the C3b molecule [
23,
24]. Furthermore, this cysteine residue forms one of the disulfide bonds in the C3 protein [
20,
25], thus its loss will likely affect protein folding and/or stability.
After vaccination for
S. pneumoniae, our patient showed a marked clinical improvement. In line with this observation, it has been shown that mice depleted for C3 by intraperitoneal injection of cobra venom factor which are immunized against
S. pneumoniae have reduced sepsis when colonized with this bacterium compared to control or neutrophil-depleted mice [
26]. Previous studies have illustrated that C3-deficient patients are able to mount adaptive immune responses to conjugated vaccines against
S. pneumoniae [
8,
9].
As mentioned, in addition to C3 deficiency the patient showed selective IgA deficiency (sIgAD). sIgAD is the most common form of primary immunodeficiency defined by decreased levels of IgA in the presence of normal levels of other immunoglobulin isotypes (reviewed in [
27]). Patients are predisposed to recurrent sinopulmonary infections, gastrointestinal disorders, autoimmune diseases, atopy and malignancies [
27,
28]. Amongst the gastrointestinal disorders, giardiasis, malabsorption, lactose intolerance, celiac disease, ulcerative colitis and nodular lymphoid hyperplasia can be found [
27]. Respiratory tract infections are the most frequent morbidities in sIgAD patients [
28], however, bronchiectasis is a rare complication [
29]. Although sIgAD is often asymptomatic, patients with concomitant IgG2 deficiency may present with impaired antibody responses against polysaccharide antigens and show predisposition to more severe bacterial infections [
28].
Besides C3 deficiency, other deficiencies of adaptive or innate immunity can also lead to increased susceptibility to infections caused by
S. pneumoniae, albeit with differences in the clinical and laboratory findings (reviewed in [
4,
12]). Two interesting examples of such innate immune deficiencies are IRAK4 and MYD88 deficiency, respectively. IRAK4- or MYD88-deficient patients are predisposed to recurrent invasive infections with
S. pneumoniae, especially meningitis (reviewed in [
12]). These patients also frequently present with impaired ability to increase plasma C-reactive protein and to mount fever in response to infection, with spontaneous improvement in adolescence (reviewed in [
12]). By contrast, our patient presented mainly with pneumonias, and similar to other C3-deficient patients [
4,
5], he showed high levels of CRP and had episodes of fever, with infectious episodes persisting throughout adolescence.
Taken together, the following observations support our hypothesis that the clinical phenotype of our patient was - at least predominantly - caused by the underlying deficiency in C3 rather than associated with sIgAD: 1) sinusitis or gastrointestinal disorders are absent in the patient; 2) bronchiectasis is observed although our patient presented with normal IgG2 levels and normal antibody responses to polysaccharide antigens; 3) the patient displays a marked and relatively specific susceptibility to infections with encapsulated bacteria such as S. pneumoniae; and 4) there was a marked clinical amelioration upon vaccination against S. pneumoniae.