| A hallmark of IRD is a substantially elevated serum level of IgG4, even if in some patients the level is in the normal range. The |
| finding of large numbers of IgG4-positive plasma cells in the affected organ, makes it likely that this is the primary source of |
| the increased IgG4 production. Yet, we want to address the quantitative aspect: does the histological analysis show a sufficient |
| number of plasma cells to explain the IgG4 level in the serum? As detailed below, there may be cases where additional sites of |
| IgG4 production are likely to be present. The following calculation depends on three estimates: (1) the daily production rate |
| needed to maintain the IgG4 level in plasma, (2) the number of plasma cells in the affected organ and (3) the |
| IgG4 production per plasma cell. |
| (1) The daily production rate of IgG for a 70 kg healthy adult is 2 g, which maintains a plasma level of 12 g/L (1200 mg/dL). |
| The IgG4 level in IRD is on average 3 g/L, which is 2.6 g/L higher than the average normal level (0.4 g/L). |
| Assuming a similar turnover, the increased IgG4 level requires a daily production of gram |
| “pathological” IgG4. |
| (2) The number of plasma cells (PCs) in the affected organ is not known, but an estimate can be made. In high-density |
| areas of affected tissue, 100 IgG4+ PCs per HPF (of 0.2 mm2) is considered convincingly positive. This corresponds to |
| 500 PCs/mm2. Assuming a section thickness of 4 μm, this would correspond to a cell density of 125000 PCs/mm3. |
| However, the same PC (average diameter 12 μm) will be visible in 3 to 4 consecutive sections, so the actual density |
| will be 37000 PCs/mm3, or 37 million PCs/cm3 tissue. Since the PCs are usually counted in areas selected for high |
| PC numbers, this is likely to be an upper limit of the number of plasma cells per gram affected tissue. |
| (3) Ig production per PC has been estimated both from in vitro and from in vivo data. In vitro, a production rate |
| of 1000 pg/PC/24 hrs has been reported [43], much higher than in vivo. The number of PCs in bone marrow, |
| spleen, and mesenteric and inguinal lymph nodes (so, without the mucosal plasma cells and contributions of scattered |
| plasma cells found all over the body) has been reported to be [44], of which some 60% () produce |
| IgG [45]. This would indicate a daily production rate of pg IgG/ PCs, or 133 pg/PC/24 hrs. |
| (4) Combining the in vivo production rate with the plasma cell numbers, a tissue mass of 1 gram (containing PCs) |
| would produce IgG4/day, which is 1.2% of the amount required to maintain an |
| IgG4 level in plasma of 2.6 mg/mL, and the average level of “pathological” IgG4 is serum. This corresponds to 86 gram |
| IgG4-rich tissue. Using the 7.5 times higher daily production rate derived from cultured cells, the value is 12 gram. |
| For a pancreas, which in pathological conditions may well be over 100 gram, the calculated required mass may seem to |
| correspond reasonably well, considering that these calculations are based on imprecise estimates. However, the actual number |
| of plasma cells in the affected organ is likely to be substantially lower than the number calculated from the counts in areas with |
| high plasma cell density (which are the areas selected during the evaluation of the histological sections). Furthermore, |
| IgG4 levels in some of the IRD patients are substantially higher than 3 g/L. Particularly in the latter patients, it is relevant to |
| note that the IgG half-life shortens at high IgG levels. This obviously increases the number of plasma cells required. It is clear |
| that we need better data, particularly on the number of IgG4 PC in a total affected tissue. Still, our calculations suggest that in |
| some Patients, other tissue sources, without obvious pathology, might be important contributors to IgG4 production in IRD. |
