Rev Esp Patol 1999; Vol. 32, N~ 3: 473-483 © Prous Science, SA. © Sociedad Espafiola de Anatomfa Patoidgica Special Session 2 © Sociedad Espaflola de Citologia Relevant topics in immunopathology Chairperson D Ferluga, Slovenia Co-chairpersons: C Nezelof, France and C Monteagudo Spain Genetically determined primary pose that the peripheral lymphoid system was made up of two com- immunodeficiencies: ponents: T-derived cells and B-derived cells. The role of thymic lesions Genetically immunodeficient animals in T-cell immunodeficiencies Nude mice, moth-eaten mice and mice with severe combined in- munodeficiency (SOlD) are the commonest immunodeficient ani- C. Nezelof mals. They are used as recipients of human tumors. All these strains present not only poor peripheral lymphoid tissue but also a La FacuIt~ de M6dicine de Paris, France. severely abnormal and underdeveloped thymic gland. The fact that the genetic disorder involves both the differentia- tion of the skin and its appendages as well as the epithelial com- The identification of inherited immunodeficiencies in humans has ponent of the thymus is indeed thought provoking. represented a major step forward in the basic knowledge of im- munology. This is because: i) it supported the notion that the sever- Thymic abnormalities in human immunodeficiencies ity and recurrence of infectious diseases are not related to the Several thymic abnormalities have been found to be associated intrinsic virulence of a given infectious agent but are directly relat- with human immune system deficiencies. ed to the failure of the host to react with an appropriate response; ii) it facilitated the subsequent individualization of a recent, wide- A genesis and ag/asia of the thvmus in DiGeorge syndrome spread and severe disease, AIDS; iii) it confirmed the dichotomy, DiGeorge syndrome includes a dysmorphic fades with micrognathia, already established in animals, between T- and B-cells and the cor- severe cardiovascular abnormalities and parathyroid hypoplasia. It is responding cellular and humoral immunities; iv) it revealed, in a true experiment of nature, certain basic molecular mechanisms rarely complete (4). Often tiny fragments of the thymic gland can be underlying the immune response as well as the pivotal role of pri- discovered upon careful dissection of the neck. These fragments are mary lymphoid organs such as the thymus in the development of made up of a histologically normal tissue (with Hassalian matura- immunity (1); and v) it opened the way over a period of less than tion), suggesting a quantitative deficit rather than a functional disor- 30 years for appropriate and effective treatment of immunodeficient der of thymic activity. disorders (2). DiGeorge syndrome results from an abnormal embryogenesis Among the various immunodeficiencies, those involving cellu- of the third and fourth pharyngeal pouch, frequently related to a lar immunity and T-cell functions have been the latest to be indi- partial monosomy of 22qllter. There is generally a close relation- vidualized. Indeed, for a long time, the functions of the thymus were ship between the severity of the cellular immunodeficiency and the unknown and methods of evaluation of the T-cells, such as cyto- amount of residual thymic tissue. The outcome is conditioned more toxic and proliferative tests, were not available (3). Within the yin- by the severity of the hypocalcemia and the cardiovascular anom- phoid tissue, the thymus stands out as a very peculiar organ (1, 3, alies than by the degree of cellular immunodeficiency. However, 4) because: i) it appears first during ontogeny; ii) it is provisional; iii) cases of DiGeorge syndrome provided the object of the first it functions mainly during fetal life and infancy; and iv) it is unique attempts at restoring immunological competence by thymic grafts. as a lymphoepithelial organ, made up of intimately admixed epithe- hal and self-renewing lymphoid elements. Thymicdysolasia in severe combined immunodeficiency The immunological role of the thymus has been established on The term of thymic dysplasia applies to all the morphological abnor- the following basis: i) experimental data; ii) the identification of malities resulting from the embryologic maldevelopment of the thy- genetically immunodeficient animals; and iii) the discovery of spe- mus gland. Dysplastic thymuses are tiny in size, weigh less than 5 g cial thymic abnormalities, such as agenesis and dysplasia in and can be easily overlooked on dissection. Lymphoid cells are human immunodeficiencies. scarce or totally absent. The epithelial cells are present but, and this is the crucial feature, they fail to differentiate into a network and to Experimental data form Hassal’s corpuscles. They remain cohesive and form solid From 1961 to 1962, J.F.A.P. Miller demonstrated that neonatal epithelial clumps (5, 6). thymectomized mice consistently developed an immunodeficient Whether this impairment in differentiation represents a primary state that preferentially affected cellular immunity and graft rejec- disorder of the thymic epithelial tissue or a secondary phenomenon tion. Comparatively, the ablation of the bursa of Fabricius in young connected with a lack of migration of a bone-marrow-derived T-cell chickens by B. Glick induced a failure to produce antibodies. These precursor is not known. In our experience, thymic dysplasia has two works were of seminal importance and led R.A. Good to pro- never been found to be associated with normal T-cell functions 473 SPECIAL SESSION 2 REV ESP PATOL and, for this reason, can be regarded as the hallmark of inherited SC/fl with profoundlymohopenia affecting both T- and B-cells T-cell immunodeficiencies and more particularly SCID. This may result from: i) reticular dysgenesis, a highly unusual con- According to the severity of the impairment of the epithelial dif- dition involving the coexistence of severe granulocytopenia with ferentiation, three types of thymic dysplasias have been described thrombocytopenia; ii) adenosine deaminase (ADA) deficiency (7), (5): i) a pseudoglandular pattern, resembling acinar pancreatic tis- an enzymatic activity involved in the clearing of toxic metabolites. sue, representing the most primitive form. This type is frequently The ADA gene is mapped to 2Oql3ter; and iii) defects in two associated with a complete absence of lymph nodes and peripher- recombinase-activating genes (RAG-i and RAG-2), the product of al lymphoid tissue (except in the spleen); ii) a simple and common which is required to make functional the rearrangement of thymic dysplasia, characterized by separate lobules and clumps of immunoglobulin and T-cell receptors (7). cytokeratin-positive epithelial cells. Usually, these epithelial cells do not elaborate a clear-cut basement membrane. Capillaries, histio- SCID with normal or high ievels of B-cells cytes, and some CD1-positive dendritic cells are present inside these epithelial clumps; iii) a thymic dysplasia with corticomedullary This represents the largerst group. In most cases, the B-cells are differentiation and pseudoatrophic pattern in which some lymphoid increased in number but remain unable to differentiate into plasma cells, either null or occasionally CD2- and CD68-positive, can be cells and to elaborate immunoglobulins and specific antibodies. found. This pattern has to be distinguished from severe thymic However, on some occasions, B-cells achieve complete plasma-cell atrophy, commonly observed in early severe malnutrition, chronic maturation associated with normal quantitative and qualitative levels viral infection such as HIV, rubella and prolonged corticoid and of immunoglobulins. This condition is commonly referred to as Neze- cyclosporin treatment. Some differential morphological features are lot’s syndrome. Described as early as 1964, Nezelof syndrome, like given in Table 1. DiGeorge syndrome, was of seminal importance since it provided the confirmation in humans of the dichotomy between the T- and B-cell systems already established in birds and mice. Despite the presence of a normal structure in the peripheral yin- Table 1. Morphological differential featuree of thymic dysplasia and severe thymic atrophy. phoid organs, that is, the presence of primary follicles (devoid of ger- minal centers) and plasma cells in lymphoid cords, patients with this Thymic syndrome are unable to produce specific antibodies (5, 7). Curiously, dysplasia Severe thymic atrophy this impairment persists after successful bone-marrow transplant Weightofthe gland <5 g >5g restoring T-cell immunity. The reason for this persistent failure of the Foliated architecture Well preserved Blurred B-cell system is not known. The patients have to be treated in the Interlobar tissue Fatly Fibroedipous same manner as those with a hypogammaglobulinemia. with inflammatory cells Apart from a few examples of purine nucleoside phosphorylase Size of the vessels Small Enlarged for the size deficiency, most cases in this category are connected with muta- of the lobules Perivescular spaces Empty Fibrohyaline deposits tions of genes encoding the common y-chain of the receptors for Epithelial maturation Totally defective Partially defective interleukins (ILs), IL-2, IL-4, IL-7, IL-9, and IL-is. The binding of IL- Hassal’s corpuscles Absent Absent or necrotic 7 to its receptor has been demonstrated to be a crucial step in nor- Cytokeratin expression Present Often reduced mal T-cell maturation (7). The gene encoding this y-chain is Lymphoid cells mapped to Xqi3 accounting for an X-linked