The Woman with SLE and Life-Threatening Pneumococcal Sepsis

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.

The Two Sides of CSF1 Receptor- Tenosynovial Giant Cell Tumour and Corticobasal Degeneration

A translocation in 1p13 leads to constitutional activation of Colony Stimulating Factor in a small proportion of synoviocytes in Tenosynovial Giant Cell Tumour (TGCT- previously called PVNS). They attract macrophages, which have the cognate receptor, CSF1R, leading to a proliferative state resembling a benign tumour in the synovium of joints or tendon sheath. The process can be localised, as in digits, or diffuse as in the knee.

So what happens if CSF1 is inactivated? The CSF1 receptor acts through and adaptor called DAP12 or TYROBP. This adaptor is also shared by another signalling entity called TREM2. When there is homozygous inactivation of either TREM2 or TYROBP, a condition called Nasu Hakola Disease results. This condition manifests as very early presenile dementia and bone cysts, often resulting in fractures. Death occurs around age 30.

Similarly, inactivating mutations of CSF1R results in a variant of Corticobasal Degeneration called Hereditary Diffuse Encepahalopathy with Spheroids.

Interestingly, heterozygous mutations in TREM2 leads to late onset Alzheimer's Disease.

Monoclonal Antibodies to CSF1R are in clinical trial for treating TGCT. The most well known is PLX3397 or Pexidartinib. A broader, more nonspecific inhibition is performed by the tyrosine kinase inhibitor Imatinib.

FcRn: Using IV Immunoglobulin to Treat Antibody Mediated Disorders

Intravenous Immunoglobulin (IVIG) is used to treat a variety of disorders. Among these conditions, a number are mediated by antibodies- such as Guillain Barre Syndrome, CIDP, Inflammatory Myositis, Multifocal Motor Neuropathy, Myasthenia Gravis & Rasmussen Syndrome.

But how do infusions of pooled antibodies from thousands of donors (each IVIG aliquot must be derived from at least a thousand donors) mitigate the consequences of pathogenic antibodies already present in the patient?

A number of mechanisms have been proposed, among them the presence of "anti-idiotype" antibodies in the infused IVIG. Thus, among the pooled antibodies, there will be a fraction that will treat the epitopes on pathogenic antibodies as "antigen" and thus neutralise them. Secondly, naive B cells binding to infused IgG through the B cell receptor will activate inhibitory ITIM motifs -"Immune Tyrosine Inhibitory Motif" and thus lead to B cell anergy. These B cells will no longer develop into memory B calls, and thus will not produce pathogenic antibodies.

While the above mechanisms are plausible, it does not explain why IVIg works well only for IgG mediated disorders such as the ones described above, but not for disorders mediated by IgM- such as MAG associated peripheral neuropathies seen in association with IgM paraprotein.

After the infusion of IVIg in subjects with pathogenic IgG antibodies such as Myasthenia Gravis, the putative IgG antibodies decline by up to 40% over a matter of several weeks. There is now sufficient evidence to suggest that this fall is due to increased degradation of these antibodies, rather than reduced production thereof.

But how does infusing IVIg increase the breakdown of intrinsic culprit antibodies?

The answer lies in a group of intracellular receptors called the "Neonatal Fc Receptor" or simply FcRn. While these were so named because they were first isolated in the gut of newborn rats, these receptors are in fact widely present in adults. The greatest concentration is in endothelial cells, but they are also found in antigen presenting cells. FcRn containing cells such as endothelial cells take up IgG by pinocytosis. In the acidic environment of endosomes-pH 6.0- FcRn binds to the Fc portion of IgG. The endosome than travels through the cell until it fuses with the cellular membrane to release the bound IgG back into the circulation. As long as sufficient FcRn receptors are available to take up circulating IgG, the effect is to recycle IgG and thus increase its half life in the circulation. However, FcRn does not bind IgM or IgA. This is the salient reason why IgG is the predominant antibody class in blood ahead of IgM and IgA- not because it's produced more, but because it is recycled repeatedly by FcRn receptors, increasing its half life, while no such thing happens with IgM or igA.


This principle is ingeniously exploited in antibody mediated diseases such as inflammatory myositides. When pooled human IVIg is infused, the "overload" of total IgG- in the infusate (more than 95% of infused IVIg is of IgG class) and intrinsic IgG- saturates the FcRn receptors. Thus, endosomal recycling is no longer possible. Instead the endosomes release pinocytosed IgG to lysosomes, where igG is degraded. Thus, infused igG leads to an overall increase in the breakdown of all IgG- including pathogenic antibodies, leading to a gradual and modest fall in the titre of pathogenic antibodies.

FcRn of course has other roles. Remember, it was first isolated in neonates. In the foetus, FcRn serves to transfer IgG across the placenta from the mother- again explaining why IgG is the only class of immunoglobulin to undergo transplacental transfer.

Recirculation of IgG has other benefits- when the amount of injected IgG is modest, i.e. the FcRn receptors are not saturated, it serves to extend the survival of monoclonal antibodies now in wide use inside the body. Again, it would not have escaped your notice that all monoclonal antibodies are of IgG class.

To summarise, FcRn explains the following observations:
1. Why IgG is the predominant class of antibody in blood
2. Infusion of IVIg reduces the level of pathogenic antibodies in humorally mediated disorders
3. Why IgG is the only class of immunoglobulin to be transferred from mother to foetus in utero
4. Why monoclonal antibodies are entirely of IgG derivation