Acquired Hemophilia A Post-COVID-19 Vaccination: A Case Report and Review.

Acquired hemophilia A (AHA) is an inhibitory coagulopathy that represents a rare variant of hemorrhagic syndromes. We present a case of idiopathic AHA in a 75-year-old male patient with a cutaneous hematoma that could be attributed to a recent COVID-19 vaccination. The aim of this report is to raise awareness of a possible association between AHA and COVID-19 vaccination and to review similar reported cases and management plans to prevent the development of possible morbidity and debilitating complications. This case illustrates an exceptionally rare side effect of the COVID-19 vaccination. The advantages of obtaining the COVID-19 vaccine outweigh the risks.

Relative inability to induce tolerance in adult NZB and NZB-NZW F1 mice.

Immunologic tolerance to ultracentrifuged bovine gamma globulin could not be induced in 6-wk old NZB or B/W mice, but developed readily in C3H, NZW, and C57Bl mice. NZB and B/W mice, as well as Balb/c mice, failed to become tolerant to ultracentrifuged human gamma globulin. The NZB and B/W mice also showed higher antibody titers to a standard antigenic challenge. This immunologic hyperreactivity and lack of experimental tolerance may be related to the lack of self-tolerance, autoimmunity, and lymphomas that develop in these mice at a later age.

Induction of immunologic tolerance in older New Zealand mice repopulated with young spleen, bone marrow, or thymus.

Newborn, 7-9 day, and 16-18 day old NZB and B/W mice were, unlike older New Zealand mice, rendered tolerant to single doses of 8-10 mg of soluble BGG. After challenge, this tolerance was of short duration and escape occurred rapidly. Age-matched and similarly treated C3H, Balb/c and C57Bl mice did not escape from tolerance. Partial tolerance could be maintained by repeated injections of BGG. Biofiltration ruled out hyperphagocytosis as an explanation for this resistance to tolerance. Tolerance could be induced in older B/W mice if they were thymectomized, irradiated, and repopulated with young (12-15 day), but not old (2-3 month), spleen or bone marrow cells. Old bone marrow cells gave a non-tolerant response even when combined with young thymic grafts. Young bone marrow gave a tolerant response which was followed by the expected rapid escape only if a young thymus graft was also present. Escape was retarded if old thymus, or old irradiated thymus, was combined with young bone marrow. These results are best explained by abnormalities of both lymphoid precursors and thymic regulation.

Synergy among lymphoid cells mediating the graft-versus-host response. I. Synergy in graft-versus-host reactions produced by cells from NZB-Bl mice.

The ability of spleen cells from young (3 month) and old (1 yr) NZB mice to induce GVH reactions in newborn C57BL/6N mice was compared quantitatively using the Simonsen spleen assay. Young NZB cells were five times more reactive than cells from older mice. The minimum number of cells producing detectable reactions was 2 x 10(6) for the young and 10 x 10(6) for the old. Young and old cells combined and injected together produced GVH reactions quantitatively similar to those obtained with inocula composed of young cells alone. Mixtures of two cell populations producing no detectable reactions when injected separately into different recipients (1 x 10(6) young cells and 4 x 10(6) old cells) produced reactions approximately equal to those obtained with 5 x 10(6) young cells. As few as 0.25 x 10(6) young cells were sufficient to effect a reaction when combined with 4.75 x 10(6) old unreactive cells. Viability of both cell populations was essential for GVH reactivity. This evidence of synergy in GVH reactions indicates that old NZB spleen cells can be rendered immunologically more reactive in the presence of a normally reactive population.

Monoclonal macroglobulinemia in NZB-NZW F1 mice.

Serum monoclonal macroglobulins were detected in over 30% of NZB/NZW F(1) mice greater than 11 mo of age. The monoclonal nature of the IgM was shown by restricted electrophoretic mobility, characteristic appearance on immunoelectrophoresis, restriction to a single light chain type, and ability to induce anti-idiotypic antisera. The monoclonal macroglobulins were separated from antibodies to DNA and RNA that migrated in the 7S region of sucrose gradients. Enlarged lymph nodes were often present in mice with monoclonal IgM, and a transplantable IgM-producing lymphoid tumor was established from the spleen of one animal.

Protective and cellular immune responses to idiotypic determinants on cells from a spontaneous lymphoma of NZB-NZW F1 mice.

A spontaneous lymphoma (141) producing monoclonal IgM is established in NZB/NZW F(1) (B/W) mice who spontaneously develop an autoimmune disease. Idiotypic determinants of 141 IgM are present on the lymphoma cell surface as shown by indirect immunofluorescence and specific cytotoxicity with rabbit anti-idiotypic antiserum. Fluorescence and cytotoxicity are inhibited by 141 IgM but not by 104E IgM, a monoclonal IgM produced by a BALB/c plasmacytoma. Immunization of B/W mice with 141 IgM before transplantation of lymphoma 141 confers protective immunity. No such protection occurs after immunization with 104E IgM or other unrelated proteins. Protected mice contain spleen cells cytotoxic for 141 lymphoma cells. This cytotoxicity is blocked by incubation of spleen cells with 141 IgM but not with 104E IgM. Moreover, splenic lymphocytes from protected mice are stimulated to synthesize DNA by 141 IgM but not by 104E IgM. These results suggest that specific cellular immune responses to idiotypic determinants may participate in the observed protection against challenge with the corresponding B-cell tumor.

Effect of castration and sex hormone treatment on survival, anti-nucleic acid antibodies, and glomerulonephritis in NZB/NZW F1 mice.

NZB/NZW F1 mice of both sexes were castrated at 2 wk of age and implanted subcutaneously with silastic tubes containing either 5-alpha-dihydrotestosterone or estradiol-17-beta. Mice receiving androgen showed improved survival, reduced anti-nucleic acid antibodies, or less evidence of glomerulonephritis as determined by light, immunofluorescent, and electron microscopy. By contrast, opposite effects were observed in castrated mice receiving estrogen. Intact male NZB/NZW F1 mice received androgen implants at 8 mo, an age when they develop an accelerated autoimmune disease associated with a decline in serum testosterone concentration. Such treated mice had improved survival and reduced concentrations of antibodies to DNA and to polyadenylic acid (Poly A). Prepubertal castration of male NZB/NZW F1 mice results in an earlier appearance of IgG antibodies to Poly A. This effect of castration was prevented if neonatal thymectomy was also performed.

Immune cell cooperation, viruses, and antibodies to nucleic acids in new zealand mice.

The development of autoimmunity in New Zealand mice is related to genetic, immunologic, and viral factors. Evidence is presented to suggest that thymus-dependent immune functions may be depressed and bone marrow-dependent functions augmented in these mice. Antibodies to RNA and DNA appear spontaneously and can also be induced by treatment with rI.rC. Antibodies binding rI.rC-(14)C in human lupus sera, in NZB/NZW F(1) (B/W) mice developing lupus, and in NZB, ALN, and ALN/NZB mice have greatest specificity for reovirus double-stranded RNA. Treatment of B/W mice with RNA and cyclophosphamide induces immunologic tolerance, and suppresses antibodies binding rI.rC-(14)C. During recovery, the specificity of the antibodies is unaltered. Induction of tolerance in this way prevents the accelerated formation of anti-RNA antibodies normally induced by MLV. This finding suggests that virus-accelerated and natural disease occur through a similar mechanism, and supports the hypothesis that viruses may act as antigenic stimuli for a genetically hyper-responsive antibody-producing system.

Autoantibodies of various specificities encoded by genes from the VH J558 family bind to foreign antigens and share idiotopes of antibodies specific for self and foreign antigens.

We examined the binding to foreign antigens and the expression of crossreactive idiotypes by a panel of 20 murine monoclonal autoantibodies encoded by V genes from the VH J558 family. 9 of 20 antibodies bound to foreign antigens such as bacterial polysaccharides, poly(Glu50, Tyr50), poly(Glu54,Lys37,Phe9), arsonate, and lysozyme, known to interact with antibodies encoded by genes from the VH J558 family. A high proportion of our panel of autoantibodies expressed crossreactive idiotypes originally borne by monoclonal rheumatoid factors, anti-Sm, and anti-DNA antibodies, all encoded by V genes from the VH J558 family. Some of these VH J558+ autoantibodies shared crossreactive idiotypes with VH J558+ antibodies directed against foreign antigens such as influenza virus hemagglutinin, poly(Glu60,Ala30,Tyr10), arsonate, and dextran. The implications of these findings are discussed with respect to the process of activation of self-reactive clones.

Deficient interleukin 2 activity in MRL/Mp and C57BL/6J mice bearing the lpr gene.

Spleen cells from MRL-lpr and B6-lpr mice have a marked defect in the ability to produce interleukin 2 (IL-2) in response to concanavalin A stimulation. This defect precedes the onset of clinical illness, increases with age, and eventually becomes virtually absolute. It is not due to cellular suppression of IL-2 production, nor does it reflect the presence of a soluble inhibitor of IL-2 activity. Failure to restore IL-2 production with macrophage-replacing factors, such as interleukin 1 and phorbol myristic acetate, suggests that IL-2 deficiency reflects a primary T cell defect rather than a macrophage defect. MRL-lpr and B6-lpr spleen cells also have an age-dependent reduction in IL-2 response that apparently results from a deficiency of cell surface receptors for IL-2. Congenic MRL-+/+ and B6-+/+ mice, which lack the lpr gene responsible for accelerated autoimmunity and lymphoproliferation, have normal IL-2 activity. These findings suggest that a defect in IL-2 activity may contribute to impaired immunoregulation in mice bearing the lpr gene. The absence of such a defect in MRL-+/+ and B6-+/+ mice further suggests that a single autosomal recessive gene is responsible for IL-2 deficiency.

Rapid loss of tolerance induced in weanling NZB and B-W F1 mice.

Young adult mice (30 to 43 days old) of autoimmune NZB and BIW F(1) strains failed to develop immunologic tolerance when treated with ultracentrifuged bovine gamma globulin and then challenged 12 days later. By contrast, weanling NZB and B/ W F(1) mice (18 to 25 days) as well as weanling C3H mice (16 to 19 days) became tolerant and had no serum antibody 12 days after challenge. The C3H mice remained unresponsive, but NZB and B! W F(1) mice produced antibody between days 27 and 41. The rapid loss of previously established tolerance to foreign antigens could have its parallel in the loss of tolerance to autoantigens with subsequent development of lupus nephritis and Coombs' positive hemolytic anemia in these animals.

Tolerance to polyinosinic-polycytidylic acid in NZB-NZW mice.

Immunological tolerance to polyinosinic * polycytidylic acid was induced in NZB/ NZW mice. This is the first experimental induction of tolerance to a nucleic antigen.

Elevated salivary and synovial fluid beta2-microglobulin in Sjogren's syndrome and rheumatoid arthritis.

Beta2-Microglobulin is normally present in low concentrations in serum and other bodily fluids. By use of a radioimmunoassay, elevated concentrations of beta2--microglobulin were found in saliva and synovial fluid from patients with Sjogren's syndrome and rheumatoid arthritis, autoimmune inflammatory diseases that attack and destroy the salivary glands and articular tissues, respectively. Elevated beta2-microglobulin concentrations decreased in the saliva of two patients who simultaneously showed a clinical response to systemic treatment. Measurement of beta2-microglobulin in inflammatory fluids may offer a simple method of quantifying local activity in autoimmune states.

Altered K+ channel expression in abnormal T lymphocytes from mice with the lpr gene mutation.

The observation that voltage-dependent K+ channels are required for activation of human T lymphocytes suggests that pathological conditions involving abnormal mitogen responses might be reflected in ion channel abnormalities. Gigaohm seal techniques were used to study T cells from MRL/MpJ-lpr/lpr mice; these mice develop generalized lymphoproliferation of functionally and phenotypically abnormal T cells and a disease resembling human systemic lupus erythematosus. The number and predominant type of K+ channels in T cells from these mice differ dramatically from those in T cells from control strains and a congenic strain lacking the lpr gene locus. Thus an abnormal pattern of ion channel expression has now been associated with a genetic defect in cells of the immune system.

Androgenic hormones modulate autoantibody responses and improve survival in murine lupus.

Antibodies to native DNA and to polyadenylic acid (Poly A) occur spontaneously and undergo a regulated switch from IgM to IgG during the course of autoimmune disease in NZB/NZW F(1) (B/W) mice. B/W females have higher titers and earlier commitment to 7S antibodies to DNA and Poly A, whereas B/W males bind DNA and Poly A primarily by 19S antibodies. We have performed castration experiments to determine the effects of sex hormones on this switch from IgM to IgG.NZB/NZW F(1) (B/W) mice were either castrated or subjected to sham surgery at 2 wk of age and studied for immunoglobulin class of antibodies to nucleic acids at 4, 6, and 7 mo post-surgery. Prepubertal castration of males caused premature death in 60% of mice. Castrated males had a significant decline in their serum testosterone concentration, an increase in DNA and Poly A binding, and an accelerated switch from 19S to 7S antibodies to nucleic acids. Castrated females had no change in mortality. However, castrated females given maintained androgen treatment had a decreased mortality compared to castrated females receiving estrogen (14 vs. 94%). The anticipated switch to 7S antibodies to Poly A was almost eliminated in castrated females. These results suggest that sex hormones modulate immunologic regulation and that androgenic hormones are protective in murine lupus.

Immunoglobulin synthesis by salivary gland lymphoid cells in Sjögren's syndrome.

The synthesis of immunoglobulins by cells infiltrating the labial salivary glands has been studied by radioimmunoelectrophoresis in 20 patients with Sjögren's syndrome (SS) and in 14 control patients with related disorders. The patients with SS were producing significantly greater quantities of IgG, IgM, and IgA. Synthesis of IgG and IgM correlated with the degree of lymphoid infiltration but not with serum immunoglobulin concentration. Patients with SS and rheumatoid arthritis (RA) showed greater synthesis of IgG and IgM than those with uncomplicated RA. The only extensive lymphoid infiltration was seen in patients with SS. One patient with SS and primary macroglobulinemia was synthesizing the paraprotein in the lip biopsy as well as in the bone marrow. These results establish the immunologic competence of the infiltrating lymphoid cells and suggest their origin from an extrasalivary source.

Comparison of different antinucleic acid antibody spectrotypes in spontaneous, induced, and murine lupus.

Sera from patients with systemic lupus erythematosus and from mice spontaneously developing lupus were subjected to isoelectric focusing by a microsucrose gradient method. The spectrotypes of human antibodies to native DNA, denatured DNA, and polyriboadenylic acid (poly A) were compared. Antibodies to native DNA and denatured DNA focused into two regions whose boundaries were pH 5.0-7.0 and pH 8.5-10.0. Antinative DNA antibodies were more homogeneous than antidenatured DNA antibodies. Anti-DNA antibodies in cryoglobulins showed more restriction than those present in serum. There was no relationship between spectrotype and pattern of disease expression. Murine antibodies to native DNA were more heterogeneous than human anti-DNA antibodies. The spectrotypes of antidenatured DNA antibodies from patients with systemic lupus erythematosus or drug induced lupus, or from an immunized rabbit, were similar. Likewise, antibodies to poly A were similar in both human and murine lupus. In contrast to anti-DNA, antibodies to poly A were restricted and focused only in the alkaline range (pH 9.5-10.0). The spectrotype of antipoly A antibodies induced by lipopolysaccharide were comparable but had an additional small band at pH 6.2. Our results suggest unique antibody spectrotypes with varying degrees of restriction for different nucleic acid antigens. Furthermore, spontaneous and induced autoantibodies have similar spectrotypes. Thus, the B cell clones producing antinucleic acid antibodies may be similar whether they are activated spontaneously, following immunization, or as a consequence of polyclonal stimulation.

Impaired Lymphocyte Transformation and Delayed Hypersensitivity in Sjögren's Syndrome.

In vitro lymphocyte transformation in response to phytohemagglutinin and streptolysin O and in vivo skin sensitization to 2,4-dinitrochloro-benzene has been studied in patients with Sjögren's syndrome and in normal controls of comparable age and sex. Both the in vivo and in vitro responses were significantly impaired in the Sjögren's patients as compared to the controls. This lack of response to mitogenic agents is probably due to an intrinsic defect in the lymphocytes rather than to a serum factor. The abnormalities were less marked in patients whose disease was localized to the parotid and lacrimal glands than in those with generalized disease, i.e., with complicating rheumatoid arthritis or pseudolymphoma.

Inhibition of antigodies binding polyinosinic-polycytidylic acid in human and mouse lupus sera by viral and synthetic ribonucleic acids.

The specificities of anti-RNA antibodies of diverse origin were studied by inhibition of the binding of radioative polyinosinic polycytidylic acid. The antibodies were from human patients with systemic lupus erythematosus (SLE), older NZB/NZW F(1) mice who have SLE, and young NZB/NZW F(1) mice immunized with either synthetic or viral double-stranded (ds) RNA. The inhibitors were two viral ds and two synthetic ds RNAs, ribosomal RNA and transfer RNA. The human sera were more heterogeneous than the mouse lupus sera, and had greatest specificity for reovirus RNA. The mouse lupus sera were more homogeneous and, in general, were inhibited efficiently by all four ds RNAs. Sera from mice immunized with synthetic RNA reacted poorly with viral RNA, whereas sera from mice immunized with viral RNA reacted with all four ds RNAs and resembled the lupus sera. These results suggest a role for viruses in the induction of anti-RNA antibodies, and are compatible with the concept that virus infection as well as excessive antibody responses are involved in the pathogenesis of SLE.

Hypogammaglobulinemia associated with accelerated catabolism of IgG secondary to its inteaction with an IgG-reactive monoclonal IgM.

Hypogammaglobulinemia due to a new pathophysiological mechanism was studied in a patient with Sjögren's syndrome, a monoclonal IgM and a mixed (IgM-IgG) cryoglobulinemia. The IgM (IgMdk) component of the cryogel possessed light chains of lambda-type with highly restricted electrophoretic mobility analagous to those of a Waldenström's macroglobulin. IgMdk reacted specifically with native IgG, with IgG subclasses 1, 2, and 4, and with the Fc piece of IgG to form a cryogel. Serum concentrations of IgG 1, 2, and 4 were 10% of normal, whereas the IgG3 level was slightly increased and the IgM level was markedly increased. Viscosity and analytical ultracentrifugation studies with the purified mixed cryogel (IgM-LgG) indicated soluble complex formation over a temperature range (36-38 degrees C) attainable in vivo. Immunoglobulin turnover studies revealed a markedly elevated rate of IgM synthesis with a normal survival of IgM, IgA, and IgE. IgG3, which failed to form complexes with IgMdk at body temperature, had a normal synthetic rate and survival. In contrast, the other IgG subclasses showed reduced synthesis and shortened survival. These studies are the first indicating a short survival of some IgG subclasses with a normal survival of another. The hypogammaglobulinemia appears to be due in part to a new mechanism of accelerated protein catabolism: The rapid elimination of IgG due to its interaction with an IgG-reactive monoclonal IgM.