Idiotype-specific intravenous immunoglobulin for therapy of immunoglobulin kappa free light chain deficiency

ABSTRACT

Deficient antibody production in patients with common variable immunodeficiency (CVID) is accompanied by an inability to produce free light chains (FLCs), particularly kappa (κ) FLC, due to B-cell dysfunction. We found that intravenous immunoglobulin (IVIg) administration, in a patient with CVID and (κ) FLC deficiency, for o short period of only 6 months, induced after discontinuation of treatment some kind of “long-lasting active immunity”, leading to the secretion of immunoglobulin (κ) FLCs. A remarkable finding of our study is how effectively IVIg therapy led to a calculable (κ/λ) FLCs ratio, within the reference range. IVIg therapy may have functioned as an idiotype vaccine which induced a humoral response. To date, several questions remain open. For instance, from a clinical standpoint, we do not know whether this form of active immunotherapy has the potential to cure or just to control the immunoglobulin (κ) FLC deficiency. Further studies are necessary to confirm these findings.

KEYWORDS:

• Intravenous immunoglobulin
• vaccine
• kappa free light chain deficiency
• common variable immunodeficiency

Introduction

The intravenous administration of exogenous pooled normal polyspecific human immunoglobulin (intravenous immunoglobulin – IVIg), obtained from a large number of healthy donors, has several clinical indications approved by United States Food and Drug Administration (FDA): primary immunodeficiencies; recurrent bacterial infections associated with B-cell chronic lymphocytic leukemia, myeloma and congenital AIDS; coronary artery aneurysms associated with Kawasaki syndrome; idiopathic thrombocytopenic purpura; after allogeneic bone marrow transplantation in the presence of infections and/or acute graft-versus-host disease.^1,2 Among all these, the clearest indication of IVIg is for patients with absent or deficient antibody production, this treatment inducing a short-term form of immunity called passive immunity. The prototype of deficient antibody production is common variable immunodeficiency (CVID), defined as a genetic immune defect characterized by significantly decreased levels of immunoglobulin G (IgG), immunoglobulin A (IgA), and/or immunoglobulin M (IgM) (with exclusion of other causes of hypogammaglobulinemia)³ and by a lack of response to protein and/or polysaccharide vaccines (these patients cannot make IgG antibodies against measles, mumps, rubella, tetanus or diphtheria toxoids, Haemophilus influenzae type b conjugate, and/or pneumococcal polysaccharide vaccines).⁴ In CVID, the number and severity of infectious complications is inversely correlated with the dose of IVIg administered.⁵ However, in recent years, the clinical use of IVIg has expanded beyond its ability to fight infection, due to its anti-inflammatory and immunomodulatory effects.

Serum free light chains (FLCs) assays are commonly used in the diagnosis and monitoring of plasma cell disorders (dyscrasias) or monoclonal gammopathies.⁶ Serum FLCs testing can detect the changes in the ratio of kappa (κ) and lambda (λ) production, which indicate a suspicion of a clonal B lymphocyte disorder. In adult individuals with normal kidney function, FLCs are present in the blood in small amounts, with a normal (κ/λ) ratio of approximately 0.26–1.65.⁷ A marked imbalance of the two light chain types of immunoglobulins has been reported in a very small number of patients unrelated to clonal B lymphocyte disorders.^8-10 Since the first case presentation in 1972,⁸ only a few patients with immunoglobulin (κ) and/or (λ) FLCs defects have been reported. In 2012, Unsworth et al. showed that CVID has been associated with a low production of FLCs, particularly (κ) FLC and suspicious (κ/λ) FLCs ratio.⁹ The most recent case was presented in 2016,¹⁰ the authors suggesting that immunoglobulin (κ) FLC deficiency could lead to an effective reduction of the variability of total antibody repertoire and a consequent defect of an apparently normal immunoglobulin response to common antigens.

In this study, we aimed to show that IVIg infusion could act as an idiotypic vaccine in a patient with CVID and immunoglobulin (κ) FLC deficiency.

Patient presentation

A 43-year-old Caucasian female was referred to our center in January 2012. The patient was diagnosed with CVID, in terms of clinical manifestations having 2 clinical phenotypes: polyclonal lymphocytic infiltration with unexplained hepatomegaly (clinical examination, ultrasound and MRI), and extensive and persistent lymphadenopathy (on palpation, ultrasound, and MRI) with autoimmunity (polyglandular autoimmune syndrome type IIIC due to the presence of autoimmune thyroiditis, autoimmune alopecia diffusa and primary ovarian insufficiency).¹¹ In our patient, no IgG was detected in urine, there was no serum paraprotein and lymphocyte immunophenotyping revealed lower than normal B cell (CD19+) count and reduced numbers of memory B cells identified by the surface marker CD27. Phenotypic analysis of peripheral B-cell subsets identified a pronounced expansion of CD21–B cells (above 10% of B cells). All patient’s laboratory data are summarized in Table 1.

Table 1. Selected patient laboratory results with corresponding reference intervals.

Variable	Results	Reference interval
IgG, g/L	5.08	8–18
IgA, g/L	1.09	0.9–4.5
IgM, g/L	0.426	0.5–3.7
Th/s (CD4+/CD8+)	1.64	1.00–3.60
B (CD19+), % (/µL)	2.72 (38)	6–19 (100–500)
NK (CD3-CD16+ CD56+), % (/µL)	14.26 (200)	7–31 (90–600)
Naive B cells (IgD+CD27-), %	78.43	43.20–82.40
Marginal zone-like/natural effector B cells (IgD+CD27+), %	19.86	7.20–30.80
Class switched memory B cells (IgD-CD27+), %	1.10	6.50–29.20
Rare (CD21-CD38-) B cells, %	23.40	0.80–7.70
Transitional B cells (IgM++CD38++), %	4.90	0.60–3.50
Plasmablasts (IgM-CD38+++), %	0.00	0.40–3.60

Three nephelometric evaluations of serum (κ) and (λ) FLCs, performed 1 year, 6 months and 3 months prior to the start of IVIg replacement therapy, demonstrated a total absence of (κ) FLCs (< 0.127 mg/L – below the limits of reliable detection) and low level of (λ) FLCs (below the reference range: 5.7–26.3 mg/L), the (κ/λ) FLCs ratio being incalculable (Table 2).

Table 2. Serum free light chains levels prior and after discontinuation of IVIg therapy.

Variable	1 year prior IVIg start	6 months prior IVIg start	3 months prior IVIg start	IVIg therapy	6 months after IVIg stop	2 years after IVIg stop	3 years after IVIg stop	4 years after IVIg stop	5 years after IVIg stop
Kappa FLCs (mg/L)	< 0.127	< 0.127	< 0.127	< 0.127	3.61	3.51	1.42	1.35	3.37
Lambda FLCs (mg/L)	3.42	4.08	3.92	2.95	3.65	4.05	1.29	1.03	3.73
Kappa/Lambda FLCs Ratio	-	-	-	-	0.98	0.86	1.10	1.31	0.90

FLCs, free light chains; IVIg, intravenous immunoglobulin.

Pooled normal human immunoglobulin OCTAGAM® 10% [100 mg/mL] from Octapharma AG (Lachen, Switzerland) was used for intravenous replacement therapy. OCTAGAM® 10%, containing at least 95% human IgG (60% IgG1; 32% IgG2; 7% IgG3; 1% IgG4) and IgA (maximum 400 mg/mL), was originally approved in Europe in 2008 for CVID treatment.¹² IVIg contain antibodies to microbial antigens, self-antigens (natural antibodies) and anti-idiotypic antibodies which recognized other antibodies.¹³ Our patient received IVIg only for 6 months (0.5 g/kg/month OCTAGAM® 10%, at three weeks interval), after which the treatment was discontinued, at the patient’s request, for no given reason. During the 6 months of IVIg replacement therapy, the measured serum FLCs were almost unchanged, as shown in Table 2.

In the next 5 years after discontinuation of IVIg replacement therapy, serum FLCs have been annually measured. Unexpectedly, 6 months after discontinuation of IVIg therapy, the patient started to produce a normal serum (κ) FLCs concentration (3.61 mg/L) (reference range: 3.3–19.4 mg/L) (Table 2). The serum level of (λ) FLCs was unchanged and the (κ/λ) FLCs ratio could be calculated, being this time within the reference range (0.26–1.65). Moreover, measurements made over the next 5 years show an average value of the (κ/λ) FLCs ratio of 1.03 ± 0.18.

Discussion

Immunoglobulin (κ) FLC deficiency is a very rare, but probably underestimated, humoral immune defect, in normal conditions, (κ) FLCs representing approximately 2/3 of the light chains of total immunoglobulins.¹⁰ During early B-cell development, the B cells from the bone marrow initiate the rearrangement of their Ig Heavy-chain genes (first) and Ig Light-chain genes (second), such that each mature B-cell and plasma cell has a unique rearranged Heavy-chain and Light-chain gene profile. This process is vital to the function of B-cells in normal immune system. Rearrangement of the Ig Light-chain starts with the (κ) locus, if the (κ) allele can be successfully paired with the Ig Heavy-chain. If the B cell is unable to rearrange both Ig(κ) alleles, as in the case of our patient, it switches to its Ig(λ) Light-chain locus.¹⁴ Ig Heavy-chain will be expressed on a pre-B-cell together with the surrogate Ig Light-chain as a pre-B-cell receptor.^15,16 In our patient, the bone marrow biopsy and aspirate showed a partial block in B-cell development at the pre-B-I to pre-B-II stage, explaining in part the inability to produce immunoglobulin light chains.

Our results obtained during the 6 months of IVIg replacement therapy were in accordance with Unsworth et al.,⁹ who found that commercial preparations of pooled normal IgG, although containing detectable (κ) and (λ) FLCs, they do not affect the level of serum FLCs in patients with CVID. The explanation is that the half-life of FLCs in the circulation is only 2–6 hours and the concentrations measured preinfusion only refers to the FLCs produced by the patient’s immune system.

However, in contrast with Unsworth et al.,⁹ who specified that FLCs did not increase when repeated weeks/months after treatment had been initiated, we found that after discontinuation of IVIg therapy, immunoglobulin (κ) FLCs increased. The difference is that in Unsworth’s study IVIg therapy was not interrupted and, in our study, IVIg therapy was interrupted. Our results clearly indicate that IVIg administration induced not only a short-term passive immunity, during the 6 months of replacement therapy, if we refer to the whole immunoglobulins, but apparently it induced some kind of “long-lasting active immunity”, if we refer to the production of immunoglobulin (κ) FLCs.

IVIg therapy may have functioned as an idiotype vaccine which induced a humoral response. Idiotype vaccination is an immunotherapy procedure based on the fact that each clone of B cells features a specific antibody on the cell surface.¹⁷ The variable regions of the immunoglobulin molecules contain determinants known as idiotypes (Id). These individual determinants show a high and continuous specificity. B cells express Id determinants which may be used for antibody targeted-therapy.

A remarkable finding of our study is how effectively IVIg therapy led to a calculable (κ/λ) FLCs ratio, within the reference range, even 5 years after discontinuation of treatment. To date, several questions remain open with respect to “IVIg vaccination”. For instance, from a clinical standpoint, we do not know whether this form of active immunotherapy has the potential to cure or just to control the immunoglobulin (κ) FLC deficiency. Although double-blind placebo-controlled studies demonstrating the benefits of IVIg for patients with immunoglobulin (κ) FLC deficiency do not exist and realistically cannot be done due to the rarity of this condition, further studies are necessary to confirm these findings.

Disclosure of potential conflicts of interest

No potential conflicts of interest were disclosed.

Additional information

Funding

This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.