Recently, I was called upon to give my opinion on an Afro Caribbean lady with well controlled SLE who had been admitted to ICU with Pneumococcal septicaemia. She was in her late 30s, had well controlled SLE with normal complements, and was on hydroxychloroquine but not steroids or other immunosuppressives. A blood film showed no evidence of Howell Jolly bodies. She had not received Pneumococcal vaccination.
Fortunately, she recovered, but it was touch and go for several weeks.
So why did the lady who was not hyposplenic, hypocomplementemic, and not on immunosuppressive agents, develop life threatening invasive Pneumococcal infection?
Invasive Pneumococcal infection is uncommon, but not rare in SLE. Around 4.7-7.1% of patients develop this infection at some point. While the other factors mentioned above may contribute, the principal risk factor is polymorphism for the FcgammaRIIa gene.(henceforth, written as FcyRIIa).
There are 3 classes of Fcy receptors- FcyRI (CD64), RFcyRII (CD32), and FCyRIII (CD16). FcvRI is a high affinity receptor that is capable of binding to monomeric Ig. The other classes are low-affinity receptors, which can only bind to multimeric or clustered Ig.
FcyRII is subdivided into FcyRIIa, FcyRIIb and FcyRIIc receptors. The first and third are activating receptors, which act through intracellular ITAM motifs, while FcyRIIb is an inhibitory receptor, that acts through ITIM motif.
FcyRI is mostly an activating receptor, although very occasionally it inhibits.
FcyRIII receptors have 2 subtypes- FcyRIIIa and FcyRIIIb. The first is present on cells of mononuclear-macrophage lineage and NK cells, while the second appears in neutrophils.
Thus, neutrophils have two principal FcyR receptors- FcyRIIa, and FcyRIIIb.
FcyRIIa has 2 alleles, depending on the presence of histidine or arginine at position 131 of the extracellular domain receptor peptide- designated as H131 or R131. They are expressed co-dominantly.
The two alleles have equal prevalence amongst Caucasians and Afro-Caribbeans. The prevalence of R131 is only 10% amongst Asians.
While all FcyR receptors bind IgG1 and IgG3 containing immune complexes well, only subjects who are homozygous for H131 at FcyRIIa bind IgG2 containing immune complexes well. Homozygotes for R131 bind IgG2 poorly, while H/R 131 heterozygotes have intermediate binding to IgG2.
This is important because IgG2 is the only class of immunoglobulins that provides protection against polysaccharide antigens present in the capsule of organisms such as Pneumococcus, Haemophilus influenzae and Meningococcus.
While IgG1 and IgG3 bind complement well, IgG2 does so poorly. Thus immune complexes containing IgG2 are inordinately dependent on Fc receptor mediated clearance, rather than complement-mediated clearance.
Several studies have shown that subjects who are homozygous for the R131 polymorphism for FcyRIIa are more susceptible to invasive Pneumococcal and other encapsulated organisms, irrespective of their complement status. Subjects who also have low complement are at even greater risk.
This is particularly true for Lupus, as the R131 allele is over-represented in Lupus- around 65%.
IgG2 antibodies are also the main subclass found in anti-C1q antibodies, thus conferring a higher risk of Lupus nephritis in R131 homozygotes. However, antibodies to C1q are uncommon, therefore the predisposition to Pneumococcal invasive infection can exist in subjects who do not have Lupus nephritis, as with the lady described above.
Similar polymorphisms exist for FcyRIIIa and FCyRIIIb.
With FcyRIIIa, present in mononuclear and NK cells, the polymorphism is F176 or V176. The former are likely to suffer more infections as they phagocytose IgG1 and IgG3 containing immune complexes poorly. Anti dsDNA and anti-nucleosome antibodies are of IgG1 or IgG3 subclass, and immune complexes containing these subclasses are cleared poorly by macrophages and monocytes, thus increasing the risk of Lupus in these subjects.
With FcvRIIIb, a GPI linked receptor present only in neutrophils, there are two alleles- NA1 and NA2. NA2 homozygotes have poor neutrophil induced phagocytosis of immune complexes compared with NA1 homozygotes and thus are at greater risk of Lupus and certain infections. Those who are homozygous for both R131 and NA2 are at risk of overwhelming meningococcal sepsis.
It is important to immunise all Lupus patients against Pneumococcus.
Fortunately, she recovered, but it was touch and go for several weeks.
So why did the lady who was not hyposplenic, hypocomplementemic, and not on immunosuppressive agents, develop life threatening invasive Pneumococcal infection?
Invasive Pneumococcal infection is uncommon, but not rare in SLE. Around 4.7-7.1% of patients develop this infection at some point. While the other factors mentioned above may contribute, the principal risk factor is polymorphism for the FcgammaRIIa gene.(henceforth, written as FcyRIIa).
There are 3 classes of Fcy receptors- FcyRI (CD64), RFcyRII (CD32), and FCyRIII (CD16). FcvRI is a high affinity receptor that is capable of binding to monomeric Ig. The other classes are low-affinity receptors, which can only bind to multimeric or clustered Ig.
FcyRII is subdivided into FcyRIIa, FcyRIIb and FcyRIIc receptors. The first and third are activating receptors, which act through intracellular ITAM motifs, while FcyRIIb is an inhibitory receptor, that acts through ITIM motif.
FcyRI is mostly an activating receptor, although very occasionally it inhibits.
FcyRIII receptors have 2 subtypes- FcyRIIIa and FcyRIIIb. The first is present on cells of mononuclear-macrophage lineage and NK cells, while the second appears in neutrophils.
Thus, neutrophils have two principal FcyR receptors- FcyRIIa, and FcyRIIIb.
FcyRIIa has 2 alleles, depending on the presence of histidine or arginine at position 131 of the extracellular domain receptor peptide- designated as H131 or R131. They are expressed co-dominantly.
The two alleles have equal prevalence amongst Caucasians and Afro-Caribbeans. The prevalence of R131 is only 10% amongst Asians.
While all FcyR receptors bind IgG1 and IgG3 containing immune complexes well, only subjects who are homozygous for H131 at FcyRIIa bind IgG2 containing immune complexes well. Homozygotes for R131 bind IgG2 poorly, while H/R 131 heterozygotes have intermediate binding to IgG2.
This is important because IgG2 is the only class of immunoglobulins that provides protection against polysaccharide antigens present in the capsule of organisms such as Pneumococcus, Haemophilus influenzae and Meningococcus.
While IgG1 and IgG3 bind complement well, IgG2 does so poorly. Thus immune complexes containing IgG2 are inordinately dependent on Fc receptor mediated clearance, rather than complement-mediated clearance.
Several studies have shown that subjects who are homozygous for the R131 polymorphism for FcyRIIa are more susceptible to invasive Pneumococcal and other encapsulated organisms, irrespective of their complement status. Subjects who also have low complement are at even greater risk.
This is particularly true for Lupus, as the R131 allele is over-represented in Lupus- around 65%.
IgG2 antibodies are also the main subclass found in anti-C1q antibodies, thus conferring a higher risk of Lupus nephritis in R131 homozygotes. However, antibodies to C1q are uncommon, therefore the predisposition to Pneumococcal invasive infection can exist in subjects who do not have Lupus nephritis, as with the lady described above.
Similar polymorphisms exist for FcyRIIIa and FCyRIIIb.
With FcyRIIIa, present in mononuclear and NK cells, the polymorphism is F176 or V176. The former are likely to suffer more infections as they phagocytose IgG1 and IgG3 containing immune complexes poorly. Anti dsDNA and anti-nucleosome antibodies are of IgG1 or IgG3 subclass, and immune complexes containing these subclasses are cleared poorly by macrophages and monocytes, thus increasing the risk of Lupus in these subjects.
With FcvRIIIb, a GPI linked receptor present only in neutrophils, there are two alleles- NA1 and NA2. NA2 homozygotes have poor neutrophil induced phagocytosis of immune complexes compared with NA1 homozygotes and thus are at greater risk of Lupus and certain infections. Those who are homozygous for both R131 and NA2 are at risk of overwhelming meningococcal sepsis.
It is important to immunise all Lupus patients against Pneumococcus.
No comments:
Post a Comment